DOI: 10.1148/radiol.2422051113
(Radiology 2007;242:360-385.)
© RSNA, 2007
PET/CT: Form and Function1
Todd M. Blodgett, MD,
Carolyn C. Meltzer, MD2 and
David W. Townsend, PhD
1 From the Departments of Radiology (T.M.B., C.C.M.), Neurology (C.C.M.), and Psychiatry (C.C.M.), University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213; and the Departments of Medicine and Radiology, University of Tennessee Medical Center, Knoxville, Tenn (D.W.T.). Received July 2, 2005; revision requested September 6; revision received September 22; accepted October 18; final version accepted April 4, 2006; final review by T.M.B. September 7. Supported by National Cancer Institute grant 65856.
Address correspondence to T.M.B. (e-mail: blodgetttm{at}upmc.edu).
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ABSTRACT
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Functional imaging with positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of malignant disease, image-guided therapy planning, and treatment monitoring. PET with the labeled glucose analogue fluorine 18 fluorodeoxyglucose (FDG) is a relatively recent addition to the medical technology for imaging of cancer, and FDG PET complements the more conventional anatomic imaging modalities of computed tomography (CT) and magnetic resonance imaging. CT is complementary in the sense that it provides accurate localization of organs and lesions, while PET maps both normal and abnormal tissue function. When combined, the two modalities can help both identify and localize functional abnormalities. Attempts to align CT and PET data sets with fusion software are generally successful in the brain; other areas of the body is more challenging, owing to the increased number of degrees of freedom between the two data sets. These challenges have recently been addressed by the introduction of the combined PET/CT scanner, a hardware-oriented approach to image fusion. With such a device, accurately registered anatomic and functional images can be acquired for each patient in a single scanning session. Currently, over 800 combined PET/CT scanners are installed in medical institutions worldwide, many of them for the diagnosis and staging of malignant disease and increasingly for monitoring of the response to therapy. This review will describe some of the most recent technologic developments in PET/CT instrumentation and the clinical indications for which combined PET/CT has been shown to be more useful than PET and CT performed separately.
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INTRODUCTION
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Functional imaging with positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of malignant disease, in image-guided therapy planning, and in treatment monitoring. PET imaging with the fluorine 18 (18F)-labeled glucose analogue 18F fluorodeoxyglucose (FDG) is a relatively recent addition to the technology for imaging cancer. FDG PET complements the more conventional anatomic imaging modalities of computed tomography (CT) and magnetic resonance (MR) imaging.
Anatomic imaging modalities are complementary to functional imaging in the sense that while CT provides accurate localization of organs and lesions, PET provides information on tissue function, both normal and pathologic. When combined, the two modalities can help both identify and localize functional abnormalities. Attempts to align or register CT and PET data sets by using fusion software are generally successful in the brain; in the remainder of the body, however, differences in scanner bed profiles, external patient positioning, and internal organ movement present a challenge to the software approaches. These challenges have recently been addressed and largely resolved by the introduction of the combined PET/CT scanner, a more hardware-oriented approach to image fusion. With this device, accurately registered anatomic and functional images can be acquired in a single examination. Having such aligned image sets routinely available has been shown to increase both the accuracy of the interpretation and the confidence level of the readers.
Current designs constitute a CT scanner in tandem with a PET scanner, with a common patient bed for both systems. Although in most designs, the scanner appears externally to be a single device, internally there is little or no mechanical integration. CT images are acquired first and are used to generate attenuation-correction factors to be applied to the PET data to correct for the effect of photon attenuation. PET data for the same axial extent of the patient are then acquired with a simple horizontal translation of the bed. On completion of the scan, coregistered CT and PET images are available for review, either separately or in fused image mode with a selectable blending of data from the two modalities.
While FDG uptake is not specific to cancer, it is well known that there is increased transport of glucose into malignant cells and upregulation of enzymatic activity resulting in increased tracer uptake. Combined PET/CT facilitates the separation of normal physiologic uptake from pathologic uptake, provides accurate localization of functional abnormalities, and reduces the incidence of false-positive and false-negative imaging studies. The imaging time for a whole-body scan is also markedly reduced, enhancing patient comfort and convenience and, if desired, increasing patient throughput.
This article will review some of the more recent technical developments and advances in PET and PET/CT instrumentation, including the use of CT-based attenuation correction. A generic protocol will be presented, with applications and case studies for a wide range of different cancers.
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PET/CT IMAGING TECHNOLOGY
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The first PET/CT prototype scanner became operational in 1998 (1). The design incorporated a spiral CT scanner with PET detectors mounted on the rear of the rotating CT assembly. Accurately aligned clinical-quality CT and PET images could, therefore, be acquired in a single examination without moving the patient from the bed. Promising results from the clinical evaluation of this device stimulated a demand from the medical imaging profession for a commercial design, a demand that drew a rapid and positive response from some of the major vendors of medical imaging equipment (2–5).
The first commercial PET/CT scanners appeared in the clinical arena in 2001, with those initial designs undergoing a number of refinements since then. One such design, manufactured by CPS Innovations (Knoxville, Tenn; now Siemens Medical Solutions Molecular Imaging Medical Solutions, Hoffman Estates, Ill) comprises a two-, six-, or 16-section spiral CT scanner (Siemens Medical Solutions, Forchheim, Germany) in the front with a PET scanner positioned at the rear. PET scanner technology has advanced rapidly in the past few years with the introduction of new faster scintillators, such as lutetium oxyorthosilicate and gadolinium oxyorthosilicate. The state-of-the-art PET scanner incorporated into the CPS Innovations PET/CT design is a lutetium oxyorthosilicate–based system with 4 x 4-mm detectors covering an axial extent of 16.2 cm. The patient port is 70 cm in diameter, to facilitate the use of the scanner for radiation therapy planning and to accommodate the increasing dimension of the average patient, particularly in the United States.
In the commercial designs, the level of hardware integration of the CT and PET scanners is fairly minimal. This has the advantage of allowing the combined device to take full advantage of the rapidly developing CT and PET technology, and the current trend has been to combine, for each new design, the highest performance CT with the top-of-the-line PET scanner. Since PET scanner performance is the limitation in terms of both spatial resolution and imaging time, the choice of the highest PET performance can usually be considered justified. However, with the introduction of multisection CT, a demand to also incorporate the highest CT performance has prevailed—a demand that is not always as well justified as it is for PET, particularly for oncologic imaging where a four or eight-section CT scanner may be adequate. The cost to customers of the combination device is actually less than the sum of the costs of the CT and PET scanners individually. However, with PET/CT now representing almost all PET sales, a demand for a lower-cost, midrange, combined scanner will inevitably arise, and it is considered likely that PET/CT scanners will replace PET-only scanners in the near future for most oncologic applications.
While many aspects of PET/CT are superior to those of PET alone, one of the more dramatic has been the overall reduction in imaging time. In addition to advances in PET scanner technology through the introduction of faster scintillators and higher-performance electronics, the use of CT-based attenuation correction has eliminated the requirement for a separate PET transmission scan. In PET-only scans, the transmission scan typically represents about 40% of the whole-body study time; therefore, replacing the transmission scan by a 45-second CT scan results in a substantial reduction in the overall study time. Thus, PET/CT examination times of 5–10 minutes are easily attainable, compared with the 45-minute scans that were standard for PET-only devices.
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CURRENT PET/CT INSTRUMENTATION
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Currently, five vendors offer PET/CT designs: the Discovery by GE Healthcare (Milwaukee, Wis), the Sceptre by Hitachi Medical Systems, the Gemini by Philips Medical Systems (Cleveland, Ohio), the Biograph by Siemens Medical Solutions, and the Aquiduo by Toshiba Medical Systems. With the exception of the SceptreP3, which is based on a four-section CT scanner and rotating lutetium oxyorthosilicate detectors, all vendors offer a 16-section CT option for higher performance, with some vendors also offering lower-priced systems with two-, four-, six-, or eight-section CT systems.
The specifications and performance of the PET components are vendor specific, with the Biograph HI-REZ offering the best overall spatial resolution in three dimensions with 4 x 4-mm lutetium oxyorthosilicate crystals; the original Biograph design was based on 6 x 6-mm lutetium oxyorthosilicate detectors. The Biograph is offered with two-, six-, 16-, and now 64-section CT scanners. The same HI-REZ PET detectors are incorporated into the Aquiduo in combination with the 16-section Aquilion CT scanner (Toshiba Medical Systems); a feature of this device is that the bed is fixed and the CT and PET gantries travel on floor-mounted rails to acquire the CT and PET data. The CT and PET scanners in the Aquiduo can be moved separately, and this is the only PET/CT design in which the CT tilt option has been preserved. The Discovery LS, the original PET/CT design from GE Healthcare, combined the Advance NXi PET scanner with a four- or eight-section CT scanner; note that there is a size difference between the smaller CT scanner in front and the larger PET scanner at the rear. The more recent Discovery ST from GE Healthcare has 6 x 6-mm bismuth germanate detectors in combination with a 16- or 64-section CT scanner; the gantry of the newly-designed PET scanner now matches the dimensions of the CT scanner. The Gemini GXL uses 4-mm (in plane) and 6-mm (axial) gadolinium oxyorthosilicate detector pixels 30 mm in depth; the Gemini is also an open design with the capability to physically separate the CT and PET scanners for access to the patient, as for the Aquiduo.
Each vendor has adopted its own design for the patient couch to eliminate vertical deflection of the pallet (Fig 1) as it advances into the tunnel during scanning. All designs other than the SceptreP3 and the Discovery LS offer a 70-cm-diameter patient port for both CT and PET, thus facilitating the scanning of patients in treatment position for radiation therapy. While the Discovery and Gemini also offer standard PET transmission sources as an option, in practice most institutions use CT-based attenuation correction because of the advantage of low noise and short scanning times that facilitate high patient throughput.
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Figure 1: Four solutions to the patient-handling system that eliminates variable vertical deflection of pallet as it advances into scanner tunnel: A, bed with fixed cantilever point where entire couch assembly moves on floor-mounted rails (Biograph, Siemens Medical Solutions; SceptreP3, Hitachi Medical Systems); B, dual-position bed with one position for CT and one for PET (Discovery LS and ST, GE Healthcare); C, patient couch incorporating a support throughout the tunnel (Gemini, Philips Medical Systems); and D, fixed couch with scanner traveling on floor-mounted rails (Aquiduo, Toshiba Medical Systems).
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The Gemini, SceptreP3, Aquiduo, and Biograph designs acquire PET data in three-dimensional mode only, whereas the Discovery incorporates retractable septa and can acquire data in both two- and three-dimensional modes. While the debate continues as to whether two- or three-dimensional acquisition yields better image quality, particularly in large patients, major improvements in three-dimensional image quality have undoubtedly been achieved through the use of faster scintillators and statistically based reconstruction algorithms. The gadolinium oxyorthosilicate (Gemini) and lutetium oxyorthosilicate (SceptreP3, Aquiduo, and Biograph) scintillators result in lower rates of both scattered photons and random coincidences, compared with bismuth germanate scintillators, and offer superior performance for three-dimensional whole-body imaging.
While there has, to date, been little effort to increase the level of hardware integration, there has been substantial effort to reduce the complexity and increase the reliability of system operation by adopting a more integrated software approach. In early designs, CT and PET data acquisition and image reconstruction were performed on separate systems that accessed a common database. Increasingly, functionality has been combined to reduce cost and complexity and to increase reliability. In the future, similar considerations of cost and complexity for the hardware may lead to greater levels of integration. The likelihood is that these designs will be application specific, incorporating eight- or 16-section CT for oncology and 64-section CT for cardiology. There will undoubtedly be a demand for more cost-effective entry-level PET/CT designs for oncology such as the Hitachi SceptreP3, with the likelihood that PET/CT will eventually replace PET-only scanners entirely.
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PET/CT OPERATION AND PROTOCOLS
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PET/CT protocols are still being defined and evaluated, and it will be a while before they become as well established as the protocols for CT (6–12). Respiration, use of intravenous and oral contrast media, CT operating parameters, PET scanning time, optimal injected dose of FDG, and other considerations must be carefully addressed before definitive PET/CT protocols for specific clinical applications will emerge. All PET/CT protocols, however, have certain common features (Fig 2).
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Figure 2: Typical imaging protocol for combined PET/CT: Topogram (A), or scout scan, is obtained for positioning. Spiral CT scan (B) is obtained, followed by a PET scan (C) over the same axial range as B. CT-based attenuation-correction factors are generated (D), and attenuation-corrected PET emission data are reconstructed (E). Finally, fused CT and PET images are displayed (F).
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As for any FDG PET scan, after injection of 10–15 mCi (370–555 MBq) of FDG and a 1-hour uptake period, the patient is positioned in the scanner. For PET/CT, the first step (Fig 2) is a topogram, or scout scan. The total range to be scanned by both PET and CT is then defined on the topogram, based on the particular indication for the study (skull base to abdomen for head and neck malignancies; neck through upper thigh for most other malignancies; head to toe for melanoma, if possible). An appropriate respiration protocol must be defined and implemented to minimize the mismatch between CT and PET. In the absence of respiratory gating, a good match is found if the CT image is acquired with partial or full expiration, and the PET image, with shallow breathing. This protocol is feasible with a 16-section CT scanner where a scan of the thorax and abdomen can be as short as 15 seconds. On completion of the spiral CT scan (Fig 2), the patient couch is advanced into the PET field-of-view, and a multibed PET study is acquired over the same range as the CT scan (Fig 2). The reconstruction of the CT images occurs in parallel with the acquisition of the PET data, allowing the calculation of attenuation-correction factors to be performed during the PET acquisition (Fig 2). The CT-based attenuation-correction factors are calculated as described in the next section; once the acquisition for the first bed position is completed, PET reconstruction can commence (Fig 2). Within a few minutes of the conclusion of the final PET bed position, attenuation-corrected and reconstructed PET images, automatically coregistered with the CT image by simply accounting for the axial shift between the CT and PET fields of view, are available for viewing (Fig 2).
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CT-BASED ATTENUATION CORRECTION
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The acquisition of accurately coregistered anatomic and functional images is obviously a major strength of the combined PET/CT scanner. An additional advantage is the use of the CT images for attenuation correction of the PET emission data. The use of the CT scan for attenuation correction not only reduces whole-body scanning times by at least 40% but also provides essentially noiseless attenuation-correction factors, compared with those from standard PET transmission measurements. Since the attenuation values are energy dependent, the correction factors derived from a CT scan at a mean photon energy of 70 keV must be scaled to the PET energy of 511 keV. The CT photon energy represents the mean energy of the polychromatic x-ray beam.
Scaling algorithms typically use a bilinear function to transform the attenuation values above and below a given threshold with different factors (13,14). The composition of biologic tissues other than bone exhibits little variation in effective atomic number and can be well represented by a mixture of air and water. Bone tissue does not follow the same trend as soft tissue because of the calcium and phosphorus content; thus, a different scaling factor is required that reflects instead a mixture of water and cortical bone. The break point between the two mixture types has been variously set at 300 and 0 HU (13,14). However, some tissue types, such as muscle (
60 HU) and blood (40 HU), have attenuation values greater than 0 HU and yet are clearly not a water-bone mix. A break point at around 100 HU would therefore appear to be optimal (Fig 3). Hounsfield units define the linear attenuation coefficients normalized to water and are thus independent of the voltage setting of the x-ray tube. The scale factor for the air-water mix below approximately 100 HU will be independent of the tube voltage. This does not apply to the water-bone mix; therefore, the scale factor for bone will be voltage dependent (15). The scaled CT images are then interpolated from the CT to the PET spatial resolution, and the attenuation correction factors are generated by reprojecting the interpolated images.
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Figure 3: Graph shows bilinear scaling function used to convert CT numbers to linear attenuation values at 511 keV. Linear attenuation coefficient at 511 keV is a function of corresponding CT value (in Hounsfield units) and is based on measurements from electron-density CT phantom with tissue-equivalent materials (Gammex 467; Gammex rmi, Middleton, Wis). Separation between soft tissue (air-water mix) and bonelike tissue (water-bone mix) is around 100 HU.
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Intravenously injected iodinated contrast medium is used in CT to enhance attenuation values in the vasculature by increasing the photoelectric absorption relative to blood, which results in a 40% change in attenuation. At the PET energy level, where the photoelectric effect is negligible, the presence of contrast medium has only a 2% effect on attenuation. However, if contrast-enhanced pixels are misidentified as being of a water-bone mix, the scaling factor will be incorrect and the erroneously scaled pixels may generate artifacts on the PET image. Many thousands of PET/CT examinations have now been performed in the presence of intravenous contrast medium, and experience has shown that contrast medium administration does not generally cause a problem that could potentially interfere with the diagnostic value of PET/CT (16).
Oral contrast medium is administered to enable visualization of the gastrointestinal tract; the distribution of the contrast material is rather variable, in terms of both spatial distribution and level of enhancement. Modifications to the basic scaling algorithm have been introduced to help distinguish oral contrast enhancement from bone attenuation values, and strategies discussed elsewhere have been developed that minimize or eliminate problems due to both intravenous and oral contrast media (6,17).
The modified algorithm can, to some extent, also reduce artifacts due to catheters and metallic objects in the patient. A more detailed discussion of artifacts arising from metallic objects can be found elsewhere (18–20). Essentially, any high-attenuation material, including contrast media, pacemakers, chemotherapy ports, prostheses, and dental hardware can cause an artifact on the PET image due to the CT-based attenuation correction. A heavily calcified lymph node can also cause an artifact and mimic malignancy. It is therefore important to check the uncorrected emission images for all studies where such an artifact is suspected.
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CLINICAL APPLICATIONS AND OVERALL PERFORMANCE OF PET/CT
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For current and future Centers for Medicare and Medicaid coverage policies for PET and PET/CT imaging, refer to the Web site http://www.cms.hhs.gov/coverage.
At the University of Pittsburgh (Pa), a prototype PET/CT scanner was used to evaluate approximately 330 patients from 1998 to 2001 (1,3–5,21–23). Since 2001, a number of studies have been performed to evaluate the general diagnostic performance of PET/CT. Hany et al (24) compared PET/CT with PET alone in 53 patients with various malignancies or possible malignancy and found respective increases in sensitivity, specificity, and accuracy from 90%, 93%, and 91% for PET to 98%, 99%, and 98% for PET/CT, with a decrease of approximately 50% in equivocal lesions for PET/CT. In another study, Bar-Shalom and colleagues (25) evaluated 204 patients with 586 suspicious lesions and found that PET/CT images offered information in addition to that from separate PET and CT images in 49% of patients and 30% of lesions. PET/CT also had a substantial effect on patient care in 14% of patients. Israel et al (26) found that PET/CT offered additional value in determining the relationship of lesions on PET and CT images in 52% of patients in a study with 91 oncology patients. In yet another study (27), lesions were notably less ambiguous on images from PET/CT (3.4%) than on images from PET alone (15.3%) and from other anatomic imaging modalities. Finally, a prospective study (28) from Essen, Germany, compared whole-body PET/CT with MR imaging in 98 patients with various malignancies. Results of that study showed PET/CT to be more accurate than MR imaging for the assessment of overall TNM stage (77% vs 54%), T stage (80% vs 52%), and N stage (93% vs 73%). Both modalities were equal for the assessment of M stage.
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UNKNOWN PRIMARY TUMORS
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A few studies have been published recently in which the role of PET/CT was evaluated in patients with cancer of unknown primary origin. Nanni et al (29) evaluated 21 patients with recently diagnosed metastatic disease without a detectable primary cancer. All patients underwent PET/CT, and occult primary lesions were identified in 57% (12 patients), compared with reported (29,30) identification with PET alone in 24%–40% of and with traditional anatomic imaging in 20%–27%. In another smaller study (31), although PET/CT images depicted more occult primary tumors (33%) than did CT and PET images viewed together (29%), PET images viewed alone (24%), and CT images viewed alone (18%), there were no statistically significant differences between the modalities.
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INCIDENTAL UNSUSPECTED MALIGNANCIES
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One of the major added benefits of PET/CT is in the ability of interpreting physicians to differentiate pathologic conditions from the many structures with physiologic FDG uptake. Typically, physiologic structures show FDG uptake that is symmetric (salivary glands), linear (muscle and bowel), and/or correlates with organs (kidneys and bladder). Although normal structures can appear asymmetric, in general patients with more asymmetric or focal FDG uptake may require further evaluation, even when a correlative CT abnormality is not seen. In one retrospective analysis of 1750 PET scans, Agress and Cooper (32) found incidental or unsuspected lesions in 53 patients, and of the 42 patients with pathologic confirmation, 71% had either malignant or premalignant lesions that differed from the malignancy for which the patient was originally referred. Ishimori and colleagues (33) examined 1912 patients who underwent PET/CT and found unexpected suspicious findings on PET images in 79 (4.1%); in those cases that correlated with a pathologic condition, malignancy was confirmed in at least 1.2%.
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BRAIN
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It is unclear what the role of hardware-based PET/CT is in the brain. CT has a limited role in the evaluation of this organ; MR imaging often provides more detail, as well as more useful information. As tracers become more specific and result in less background uptake, it will be more important to have accurately coregistered PET and CT images. At the University of Pittsburgh, all patients referred because of neurologic indications are still examined with a dedicated PET scanner rather than with a PET/CT scanner.
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HEAD AND NECK
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Many of the studies to date in which patients with head and neck malignancies were evaluated have been performed in patients with squamous cell carcinoma (SCC) and various thyroid malignancies. Less common malignancies have not been well studied with PET or PET/CT. The focus of this article for head and neck malignancies will be on SCC.
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SCC OF THE HEAD AND NECK
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The use of PET/CT has reduced the incidence of pitfalls and allows easy differentiation of physiologic from pathologic FDG uptake, more accurate localization of lesions, and detection of lesions without an anatomic correlative abnormality (34–41). Physiologic structures such as muscle and brown fat are easily distinguishable from abnormalities on PET/CT images, whereas with PET images alone, with or without CT correlation, differentiation can be challenging or impossible and can lead to unnecessary further evaluation (Fig 4).
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Figure 4a: Recently diagnosed cervical carcinoma in a 33-year-old woman with a focal abnormality on coronal PET image (not shown) in area of right adrenal gland. (a) Transverse CT image is normal through level of right adrenal gland and area posterior to the gland (arrow). (b) Transverse fused PET/CT image shows intense focal area of FDG uptake (arrow) just posterior to normal right adrenal gland. Fused image allowed precise localization to perirenal fat, indicating focal FDG uptake in brown fat. At follow-up 5 months later, FDG accumulation was not present.
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Figure 4b: Recently diagnosed cervical carcinoma in a 33-year-old woman with a focal abnormality on coronal PET image (not shown) in area of right adrenal gland. (a) Transverse CT image is normal through level of right adrenal gland and area posterior to the gland (arrow). (b) Transverse fused PET/CT image shows intense focal area of FDG uptake (arrow) just posterior to normal right adrenal gland. Fused image allowed precise localization to perirenal fat, indicating focal FDG uptake in brown fat. At follow-up 5 months later, FDG accumulation was not present.
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A recent study (42) from the University of Pittsburgh showed the incremental value of PET/CT images over PET and CT images interpreted separately: PET/CT had an overall sensitivity of 98%, specificity of 92%, and accuracy of 94% for the evaluation of patients known to have or suspected of having SCC of the head and neck. That study also showed that for all lesions (n = 125), CT was inferior to PET and PET was inferior to PET/CT and that 62% of lesions considered equivocal on CT images and 41% of lesions considered equivocal on PET images were categorized more definitively when readers had access to fused PET/CT images.
In another similar study, Shoder and Yeung (43) compared PET and PET/CT in patients with any malignant lesion of the head and neck and found that PET/CT had a higher accuracy for depicting cancer than did PET alone (96% vs 90%). In a total of 157 lesions in that study, PET/CT provided improved localization in 100, compared with PET alone, and 53% of equivocal lesions were classified more confidently on the basis of PET/CT images.
Initial Diagnosis
Patients with SCC with no mucosal primary tumor identified represent 1%–5% of all patients in whom SCC is diagnosed. PET has been studied in this patient population, with a sensitivity ranging from 5%–60%, but results from larger studies suggest a sensitivity in the range of 25%–35% (44–51). Preliminary results (52,53) suggest that combined PET/CT may offer a slight increase in overall sensitivity (33%–57%) for detection of unknown primary tumors, but it may offer substantially more information to assist in biopsy localization (Fig 5).
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Figure 5a: Recently diagnosed metastatic SCC of right side of neck with no detectable mucosal lesions present in a 55-year-old man. (a) Transverse CT image shows no detectable abnormality in area of right base of the tongue (arrow). (b) Transverse fused PET/CT image shows focal asymmetric area of intense FDG uptake (arrow) in right base of tongue, confirmed at subsequent biopsy to be the mucosal primary lesion.
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Figure 5b: Recently diagnosed metastatic SCC of right side of neck with no detectable mucosal lesions present in a 55-year-old man. (a) Transverse CT image shows no detectable abnormality in area of right base of the tongue (arrow). (b) Transverse fused PET/CT image shows focal asymmetric area of intense FDG uptake (arrow) in right base of tongue, confirmed at subsequent biopsy to be the mucosal primary lesion.
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Staging
Syed et al (54) showed that PET/CT substantially increases interobserver agreement and confidence levels in localization of lesions for staging of SCC. Several studies (55–62) have shown the benefit of PET in evaluation of regional nodal spread, particularly when normal-sized malignant lymph nodes have been detected. PET/CT can add more localization information, such as the precise nodal levels involved and even which of the nodes within a level are abnormal. It can also show contralateral disease that may not be seen on CT images alone, which has a drastic effect on patient care because contralateral spread usually requires bilateral, rather than unilateral, radical neck dissection. Authors of a few reports (56,63–65) have also suggested an important role for PET/CT in radiation therapy planning; their studies have often shown an increase in gross tumor volume when PET data were incorporated. For staging of SCC in the head and neck, PET/CT has also been reported to be helpful in delineating perineural spread of disease and can show osseous extension of the primary tumor that may affect the surgical approach (66). In addition, PET/CT can be helpful in allowing further characterization and evaluation of additional foci of FDG uptake outside of the neck region, which may represent a second primary malignancy or metastatic spread of the head and neck cancer (33,67).
Restaging
PET and, more recently, PET/CT have been shown to be more sensitive (88%–100%) and specific (75%–100%) than CT (sensitivity, 38%–90%; specificity, 38%–85%) for the detection of recurrent or residual disease at the primary site, as well as the detection of nodal recurrence (59,68–81). The added ability of PET/CT to help accurately localize disease makes it more appealing than PET alone, which can help determine the presence of disease but with which precise localization is often difficult (Fig 6).
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Figure 6a: PET/CT restaging in 56-year-old man after radical neck dissection and radiation therapy. (a) Coronal PET image shows focal abnormality (arrow) in neck region to the right of midline. Further localization is difficult with PET alone. (b) Transverse CT image shows extensive posttreatment changes (arrow), with loss of fat planes and architectural distortion but no definite evidence of tumor recurrence. (c) Transverse fused PET/CT image shows two foci (arrows) of moderate to intense FDG uptake in right parapharyngeal space.
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Figure 6b: PET/CT restaging in 56-year-old man after radical neck dissection and radiation therapy. (a) Coronal PET image shows focal abnormality (arrow) in neck region to the right of midline. Further localization is difficult with PET alone. (b) Transverse CT image shows extensive posttreatment changes (arrow), with loss of fat planes and architectural distortion but no definite evidence of tumor recurrence. (c) Transverse fused PET/CT image shows two foci (arrows) of moderate to intense FDG uptake in right parapharyngeal space.
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Figure 6c: PET/CT restaging in 56-year-old man after radical neck dissection and radiation therapy. (a) Coronal PET image shows focal abnormality (arrow) in neck region to the right of midline. Further localization is difficult with PET alone. (b) Transverse CT image shows extensive posttreatment changes (arrow), with loss of fat planes and architectural distortion but no definite evidence of tumor recurrence. (c) Transverse fused PET/CT image shows two foci (arrows) of moderate to intense FDG uptake in right parapharyngeal space.
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Prognosis
Standardized uptake values obtained from FDG PET scans have been shown to correlate with tumor-free intervals and overall prognosis, although no studies have been conducted to evaluate the possible additional prognostic value of PET/CT in the head and neck (79).
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THYROID CARCINOMA
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Initial Diagnosis and Staging
Although more aggressive forms of thyroid carcinoma have been reported to show FDG uptake at the time of diagnosis, most well-differentiated thyroid malignancies are not FDG avid early in the disease process. There is a well-described "flip-flop" phenomenon, first reported by Feine et al (82), in which there is an apparent temporal reversal of FDG and iodine uptake by tumors. Many well-differentiated thyroid malignancies that are initially iodine avid do not demonstrate much FDG uptake. Over time, lesions may show partial or complete reversal of iodine and FDG avidity, making them potentially good candidates for PET or PET/CT. In addition, a large percentage of metastatic lesions from well-differentiated thyroid malignancies are initially iodine avid, and several early studies showed that when FDG is used PET demonstrates low sensitivities for the detection of metastatic lesions. The largest study of which we are aware (83) of patients with differentiated thyroid cancer showed FDG PET to have a sensitivity of 75% and a specificity of 90%.
Restaging
Despite the variability observed with FDG for staging in patients with thyroid malignancy, the use of FDG PET is well documented in patients with a negative iodine 131 (131I)-enhanced scan and an increasing thyroglobulin level. The sensitivity of FDG PET in this select group of patients can be as high as 94% (84–88). Ong et al (89) evaluated the use of PET/CT in 17 patients with rising thyroglobulin level and negative 131I scans after thyroidectomy and found lesions in 15 patients, for a sensitivity of 88.2%. More recently, Nahas and colleagues (90) evaluated the use of PET/CT in 33 patients suspected of having recurrent papillary carcinoma and found a specificity and positive predictive value of 100% each.
Other types of thyroid malignancies have been less well evaluated with FDG PET, but sensitivities of up to 92% for Hürthle cell cancer and 78% for medullary carcinoma have been reported (91,92). In our experience, PET/CT has been helpful in localizing lesions that were not apparent on CT images in patients with a rising thyroglobulin level and a negative 131I scan (Fig 7) (93).
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Figure 7: Transverse fused PET/CT image in a 39-year-old woman with history of thyroid carcinoma, recent increase in thyroglobulin level, and negative 131I scan after thyroidectomy shows small focal area of intense FDG uptake (arrow) correlating with 6-mm normal-sized lymph node just anterior to left jugular vein.
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LUNG CANCER
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Initial Diagnosis: Solitary Pulmonary Nodule Evaluation
The utility of PET in the evaluation of pulmonary nodules has been the subject of several studies, many of which have shown the sensitivity and specificity of FDG PET to be approximately 90% (94–96). In most evaluations, the sensitivity tends to be higher than the specificity, which is due to the lack of specificity of FDG, and when fungal infections or other infectious or inflammatory processes are prevalent, the specificity tends to be even lower. It is likely that the additional information garnered from the CT portion of a combined PET/CT scan will help improve the specificity over that of PET alone. However, to our knowledge, no studies have yet directly compared the performance of PET with that of PET/CT for the evaluation of pulmonary nodules.
A meta-analysis summarized the data for 1474 nodules from 40 studies and showed that the overall combined sensitivity and specificity of FDG PET was 91.2%, although a sensitivity of 96.8% and a specificity of 77.8% were more reflective of the findings in clinical practice (97).
Although several studies have shown the utility of FDG PET and PET/CT in the evaluation of solitary pulmonary nodules (PET and PET/CT are not generally indicated for multiple pulmonary nodules), there are several potential limitations in clinical practice that need to be considered. For instance, several nonmalignant inflammatory and infectious processes, such as tuberculosis and fungal infections, can take up FDG and mimic the appearance of a malignant nodule on PET or PET/CT images (94,98–100). Sarcoidosis, silicosis, and other granulomatous processes can also appear similar to malignant nodules. Therefore, it is necessary to know details about the patient regarding exposure, as well as pertinent medical history (98,101). In addition, the CT portion of a combined PET/CT scan can often provide additional information for further characterization of pulmonary nodules (Fig 8).
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Figure 8a: PET/CT evaluation of upper lobe pulmonary nodule in 54-year-old man. (a) Transverse CT image shows single upper lobe cavitary nodule (arrow). (b) Transverse fused PET/CT image shows intense focal FDG uptake (arrow). Malignancy, fungal infection, and tuberculosis were appropriately included in differential diagnosis. Although all can have a similar appearance, this was tuberculosis, an important cause of positive PET images that can be misinterpreted as malignancy.
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Figure 8b: PET/CT evaluation of upper lobe pulmonary nodule in 54-year-old man. (a) Transverse CT image shows single upper lobe cavitary nodule (arrow). (b) Transverse fused PET/CT image shows intense focal FDG uptake (arrow). Malignancy, fungal infection, and tuberculosis were appropriately included in differential diagnosis. Although all can have a similar appearance, this was tuberculosis, an important cause of positive PET images that can be misinterpreted as malignancy.
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There is some evidence to suggest that "dual-time-point" imaging may also be helpful in differentiating malignant versus inflammatory and infectious processes (98,102,103). This involves performing the first PET or PET/CT examination at the usual time after FDG injection (approximately 1 hour) and then performing another examination at a later time (average of 2–4 hours after FDG injection). The reasoning behind this delayed second examination is that malignant nodules generally tend to continue to accumulate FDG over time, whereas inflammatory and infectious processes tend to show less FDG uptake over time. By obtaining images at more than one time point, it is possible to determine the trend of FDG uptake.
Although newer PET scanners capable of higher resolution have an intrinsic spatial resolution close to 4 mm, most scanners in use today can, in general, depict 6–12-mm lesions as long as they are relatively metabolically active. However, false-negative scans can be seen in primary or metastatic nodules that are less metabolically active, such as bronchioalveolar cell carcinoma (BAC) (104,105). Even a 3-cm BAC may not be detected on FDG PET or PET/CT images owing to the lack of FDG uptake; in fact, BAC may be undetectable on FDG PET images up to 57% of the time (Fig 9) (105). Another primary tumor with reportedly low relative FDG uptake is carcinoid tumor, which like BAC, can be a cause of false-negative PET images (106). However, FDG PET has a very high negative predictive value for solitary pulmonary nodules, so a patient who may not tolerate an invasive procedure can be followed up with serial CT to help assess stability or resolution of disease.
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Figure 9a: Images in 76-year-old woman with right lower lobe pulmonary nodule who was referred for evaluation by PET/CT. (a) Coronal FDG PET image shows no abnormality. (b) Transverse fused PET/CT image shows no uptake in nodule (arrow), suggesting a benign process. Follow-up CT showed increase in size, and subsequent biopsy showed bronchioalveolar cell carcinoma, a common cause of false-negative PET images.
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Figure 9b: Images in 76-year-old woman with right lower lobe pulmonary nodule who was referred for evaluation by PET/CT. (a) Coronal FDG PET image shows no abnormality. (b) Transverse fused PET/CT image shows no uptake in nodule (arrow), suggesting a benign process. Follow-up CT showed increase in size, and subsequent biopsy showed bronchioalveolar cell carcinoma, a common cause of false-negative PET images.
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Standardized uptake values (SUVs) with PET alone have been used to help differentiate a benign from a malignant lesion, with an SUV of 2.5 often being cited as a guideline for the cutoff between uptake in benign (SUV < 2.5) and that in malignant (SUV 
2.5) processes. Where SUVs are used to help evaluate a response to therapy, it is important to use the same scanner, since SUVs can differ markedly between scanners that are not cross calibrated. Most physicians who are experienced at interpreting PET images advocate the use of SUVs for therapy purposes rather than for the differentiation of benign from malignant processes, where qualitative assessment is usually more important.
PET/CT can often be helpful in the precise localization of pulmonary lesions, particularly when there are lesions adjacent to structures with physiologic FDG activity, such as the heart. With nodules more centrally located in the lung parenchyma, this benefit is less noticeable because there is little background FDG activity. However, when there is more than one nodule in the same region, the increased localization information becomes much more apparent (Fig 10). In addition, results of a recent study (107) suggest that accurate retrospective coregistration of PET and CT data sets is possible in the thorax, as long as the anatomic positioning of the patient and respiratory instructions are carefully matched.
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Figure 10a: Multiple pulmonary nodules in 73-year-old woman. (a) Coronal PET image shows only one FDG-avid lesion (arrow) in right lung. This patient had three nodules, however: two in right lower lobe and one in left lower lobe (not shown) adjacent to the heart. (b) Transverse fused PET/CT image shows which of the two nodules is FDG avid (arrow). Results of subsequent directed biopsy of FDG-avid lesion in right lower lobe showed adenocarcinoma. All three lesions were surgically removed. The second right lower lobe lesion (arrowhead) was focal peripheral infarct from tumor emboli of the more proximal lesion, and left lower lobe lesion was a hamartoma.
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Figure 10b: Multiple pulmonary nodules in 73-year-old woman. (a) Coronal PET image shows only one FDG-avid lesion (arrow) in right lung. This patient had three nodules, however: two in right lower lobe and one in left lower lobe (not shown) adjacent to the heart. (b) Transverse fused PET/CT image shows which of the two nodules is FDG avid (arrow). Results of subsequent directed biopsy of FDG-avid lesion in right lower lobe showed adenocarcinoma. All three lesions were surgically removed. The second right lower lobe lesion (arrowhead) was focal peripheral infarct from tumor emboli of the more proximal lesion, and left lower lobe lesion was a hamartoma.
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Several other tracers have been and continue to be developed, and these show promise either as alternatives or as a complement to FDG. The one that has seen the most use so far is a thymidine analog, 18F-3'-fluoro-3'-deoxy-L-thymidine (FLT) (108–112). As a marker of cellular proliferation, this tracer should theoretically be more specific for neoplasms, particularly for tumors that have a high rate of cellular proliferation. However, preliminary results have been mixed with regard to the ability of FLT to enable distinction between tumor and infection and inflammation. Most of these studies have reported some false-positive and some false-negative images. In addition, there is also intense background physiologic FLT uptake in both the liver and the bone marrow, making FLT less appealing as a single tracer.
Although few data exist demonstrating the utility of PET/CT for directing biopsy, this is certainly a potentially useful application that is underutilized. The added localization information that is available on fused PET/CT images is useful in determining which nodule or portion of the nodule should be subjected to biopsy.
Staging
Lung cancer is typically divided into small cell and non–small cell subtypes. Most patients with small cell lung cancer are thought to have systemic disease at diagnosis and are typically not considered to be surgical candidates, with rare exceptions. This review will be limited to a discussion of non–small cell lung carcinoma.
Non–Small Cell Lung Cancer
PET alone has not been shown to be particularly useful in determining the T status of the primary lesion and is generally not helpful for determining chest wall involvement. However, because CT is better at predicting chest wall involvement, PET/CT would intuitively seem to be the preferred modality. A recent study by Cerfolio et al (113) showed that PET/CT more accurately predicted T status (70% of cases) than did PET alone (47%).
In the more important role of assessing the mediastinum, several studies have shown FDG PET to be more accurate than CT (Fig 11). In one of the largest studies (114) in which PET was compared with CT for evaluation of the mediastinum, PET was shown to have a sensitivity and specificity, respectively, of 91% and 86%, compared with 75% and 66% for CT. Although size criteria are often helpful for the radiologist in determining whether a node is malignant, there is poor correlation between nodal size and the presence of metastatic disease in the mediastinum, with metastatic disease present in 21% of normal-sized nodes, while up to 40% of enlarged nodes are free of malignancy (115–117). In addition, evaluation with PET has been shown to reduce the number of futile thoracotomies by up to 41%, relative to the rate from conventional work-up, usually by showing the presence of unsuspected contralateral mediastinal involvement or distant metastases (118–120). Several other studies (121–123) have shown that PET imaging is more sensitive and specific than CT and can change patient care up to 67% of the time.
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Figure 11a: Staging PET/CT in 58-year-old man with recently diagnosed with SCC of left lower lobe. (a, b) Transverse PET/CT images show large left lower lobe primary lesion and intense uptake in slightly enlarged contralateral right paratracheal and subcarinal lymph nodes (arrows), corresponding to stage IIIB disease. Although the nodes were seen on CT images (not shown), the additional PET information raised the confidence level of the interpreting physician for determining the presence of tumor in the nodes.
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Figure 11b: Staging PET/CT in 58-year-old man with recently diagnosed with SCC of left lower lobe. (a, b) Transverse PET/CT images show large left lower lobe primary lesion and intense uptake in slightly enlarged contralateral right paratracheal and subcarinal lymph nodes (arrows), corresponding to stage IIIB disease. Although the nodes were seen on CT images (not shown), the additional PET information raised the confidence level of the interpreting physician for determining the presence of tumor in the nodes.
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Lardinois et al (124) showed that integrated PET/CT provided additional information in 20 (41%) of 49 patients, beyond that provided by conventional visual correlation of PET and CT images. Antoch and colleagues (125) compared PET, CT, and PET/CT for staging in 27 patients with non–small cell lung cancer and found that PET/CT had a higher sensitivity, specificity, and accuracy (89%, 94%, and 93%, respectively) than did PET (89%, 89%, and 89%, respectively) or CT (70%, 59%, and 63%, respectively). PET/CT was also shown to be significantly more sensitive for evaluating the American Thoracic Society nodal stations 4R, 5, 7, 10L, and 11 and was more accurate than PET for evaluating stations 7 and 11 (113).
In addition, PET/CT has been shown to depict more distant metastatic lesions than do other imaging modalities at the time of staging (125). The presence and precise localization of extrathoracic metastases are better evaluated with PET/CT because of its ability to depict small lesions that may not show mass effect, enhancement, or necrosis.
In recent years, many of the radiation therapy planning systems have been upgraded to be able to incorporate both CT and PET data sets. Many also have the ability to fuse the two data sets by using the planning software. Some preliminary studies have shown that radiation portals and tumor volumes change up to 50% of the time when both PET and CT data sets are considered, compared with the traditional CT planning method (126). This anatomic and functional plan has the biggest effect when there are portions of a tumor that may not be visible or are not included on CT images alone. With both the anatomic and metabolic data, radiation oncologists are able to define viable tumor volume more accurately, as well as minimize the amount of exposure to normal tissue.
Restaging
Following extensive surgery or radiation, it is fairly common to have some degree of scarring within the remaining lung parenchyma. Serial CT to identify areas of growth or change is typically used to follow these patients up. With PET and PET/CT, most of these patients can be evaluated more accurately and earlier than with other imaging modalities. Much of the FDG uptake due to inflammation from surgery resolves relatively quickly (typically within 6 weeks), and these patients can be reevaluated at this time for residual or recurrent tumor, particularly patients in whom the margins may not have been clear. In the restaging evaluation of patients with lung cancer, one of the most challenging aspects is differentiating recurrent or residual tumor from posttherapy changes. Both processes can appear identical on CT images, which presents a challenge to the use of this modality in the posttreatment patient with lung cancer. Conversely scar and fibrosis are, by definition, dead tissue and should not result in any FDG uptake, which makes PET or PET/CT ideal for this indication. PET has been shown to have a sensitivity of 98%–100% for the differentiation of tumor from posttreatment changes in the lung (127,128).
Radiation pneumonitis is a cause of false-positive FDG PET images. In addition, evaluation of the primary tumor is generally not possible in the setting of radiation pneumonitis. Because of the radiosensitivity of the lung, patients who have undergone irradiation to the lungs are not typically reevaluated for 2–4 months after their last treatment (Fig 12). However, the inflammatory effects of radiation can last more than a year (129,130).
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Figure 12a: Images in 53-year-old man who underwent reevaluation just 5 weeks after receiving high-dose radiation to medial portion right lung because of adenocarcinoma. (a) Transverse CT image shows geographic areas of parenchymal changes (arrow) corresponding to radiation portal; findings are compatible with radiation pneumonitis. (b) Transverse fused PET/CT image shows diffuse intense FDG uptake (arrow) in corresponding abnormality, making any assessment of underlying tumor impossible. Typically, patients should not be referred for FDG PET for 2–3 months after radiation treatment.
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Figure 12b: Images in 53-year-old man who underwent reevaluation just 5 weeks after receiving high-dose radiation to medial portion right lung because of adenocarcinoma. (a) Transverse CT image shows geographic areas of parenchymal changes (arrow) corresponding to radiation portal; findings are compatible with radiation pneumonitis. (b) Transverse fused PET/CT image shows diffuse intense FDG uptake (arrow) in corresponding abnormality, making any assessment of underlying tumor impossible. Typically, patients should not be referred for FDG PET for 2–3 months after radiation treatment.
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ESOPHAGEAL CANCER
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In 2005, the American Cancer Society estimated that there would be 14 500 new cases of esophageal cancer diagnosed in the United States, with approximately 13 500 deaths (131). There is little evidence supporting the use of PET and PET/CT for initial diagnosis or for differentiation of benign from malignant processes in either asymptomatic or symptomatic patients without a diagnosis of esophageal cancer. A variety of nonmalignant causes of FDG uptake that may mimic malignancy, including reflux and radiation-induced esophagitis, have been described in the PET and PET/CT literature (132–134). Other pitfalls include focal areas of paraesophageal brown fat, asymmetric uptake in the vocal cords, and atherosclerotic disease in the aorta and great vessels (37,40,135–138). Although these may be impossible to differentiate from areas of esophageal uptake on PET images alone, they are generally easily differentiated on PET/CT images. In addition, FDG PET images may be false-negative with regard to identifying the primary tumor in up to 20% of cases, particularly in patients with well-differentiated adenocarcinoma (139,140).
Staging
Most studies evaluating the ability of PET and PET/CT to help stage patients with newly diagnosed esophageal carcinoma showed the major benefit to be that of determining the M status of the patient. The results of many studies (139–144) have confirmed the inability of PET findings to serve as accurate predictors of T or N status owing to the relatively low sensitivity of PET. A prospective study of 74 patients by Flamen et al (143) showed PET to have a sensitivity of only 33%, compared with 81% for endoscopic ultrasonography (US), confirming earlier results (139,140) from the University of Pittsburgh that showed the sensitivity of PET for local-regional nodal involvement to be 41%–45%. However, in a smaller study by Flanagan et al (141), the sensitivity of PET for detection of local-regional nodal involvement was considerably higher (76%) than that in other studies and was also higher than that of CT (45%). More recently, Kato et al (142) evaluated 149 patients for the potential incremental value of PET over CT and found that, with regard to staging, PET had a 14% overall incremental value over CT. However, they also reported a similarly low sensitivity for regional lymph node detection (32%).
The utility of PET and PET/CT in helping determine local-regional nodal involvement is a consequence of the high specificity, where observed nodal disease is highly suspicious for metastatic involvement (139–143). PET/CT will likely offer some diagnostic improvement over PET or CT performed separately; Bar-Shalom and colleagues (144) recently reported that PET/CT had an incremental value over PET alone for interpretation of 25 (22%) of 115 sites and offering increased confidence and improved lesion localization in 15%. In that study, PET/CT also demonstrated improved specificity and accuracy over PET alone for the detection of sites of esophageal cancer.
For M staging, PET has been shown to be more sensitive and accurate than CT or endoscopic US in helping detect distant metastatic disease (139,140,145–147). PET/CT has also been shown to be helpful in changing management in the staging of esophageal cancer. In the study by Bar-Shalom et al (144), PET/CT had a further effect in 10% of patients (in agreement with the change in patient care reported in several PET-only studies), where PET/CT findings suggested a change in surgical management in up to 20% of cases (141,144,146). However, in two patients, fused images were helpful in differentiating benign FDG uptake from otherwise suspicious FDG activity seen on PET-only images.
A few investigators have recently evaluated the role of PET- or PET/CT-based radiation treatment planning. Konski et al (148) suggested that PET and endoscopic US may be beneficial in determining gross tumor volume; in another study, however, Vrieze and colleagues (149) showed a high rate of mismatch between a negative PET image and obvious tumor as seen on CT or endoscopic US images, cautioning that treatment volume should not be decreased on the basis of a lack of FDG uptake. In patients who had undergone neoadjuvant chemotherapy and radiation therapy, the accuracy for determination of correct nodal status of PET/CT was recently reported (150) to be equal to that of endoscopic US with fine-needle aspiration (80% for both) and superior to that of CT (76%). PET/CT was also more accurate (93%) than both CT (78%) and endoscopic US with fine-needle aspiration (78%) with regard to predicting T status (differentiating T4 from T1–T3), as well as more accurate in predicting complete response to therapy (89%), compared with results of US and aspiration (67%) and CT (71%) (150).
Restaging
Although PET has been shown to be extremely helpful in the posttreatment patient, several cases of false-positive images have been reported after therapy, which reduces the specificity of PET, particularly in the early posttherapy period (132,133). However, FDG PET has been shown to have a sensitivity and specificity, respectively, of 100% and 57% for detection of local recurrence, 92% and 83% for detection of regional disease recurrence, and 95% and 80% for detection of distant disease, compared with those values for traditional anatomic imaging methods, which have been shown to be 83% and 92% for regional recurrence and 80% and 70% for distant recurrence (151).
FDG PET also has prognostic value. Swisher et al (152) found a standardized uptake value greater than 4 to be an independent predictor of survival in a study with 103 patients.
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BREAST CANCER
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Initial Diagnosis
The results of early studies by several groups (153–156) suggested that PET may have a high sensitivity for the detection of primary breast lesions larger than 1 cm. In the largest study to date, however, Avril and colleagues (153) found that almost 40% of primary breast carcinomas smaller than 2 cm were not seen on PET images obtained with the use of FDG. There is a paucity of studies evaluating the role of FDG PET in patients with lesions smaller than 1.5 cm. On the basis of the data presented by Avril et al, it is unlikely that FDG PET or PET/CT will play a major role in the screening process for breast cancer in the near future. However, most studies have suggested that FDG PET has a high positive predictive value, so an incidental lesion or a lesion seen in a symptomatic patient should be considered malignant until proved otherwise; the absence of FDG uptake in the breast does not exclude the presence of disease.
Staging
Several studies (154–164) performed to evaluate PET for examination of the axilla have shown variable sensitivity (33%–100%) and specificity (66%–100%), depending on the type of interpretation (sensitivity vs specificity) and the size criteria used. Results from three early studies (155,156,165) suggested that FDG PET may be helpful in evaluating the axilla; however, these studies included relatively few subjects. In a larger study, Adler et al (161) evaluated 50 patients and reported FDG PET to have a sensitivity and a negative predictive value of 95% each and an overall accuracy of 77%. For sensitivity interpretations, there were 11 false-positive findings, with a specificity of only 66%. In another study, with 51 patients, Avril and colleagues (163) found a sensitivity and specificity of 79% and 96%, respectively; however, when only patients with late-stage disease were considered (primary breast tumor > 2 cm, stage > pT1), the sensitivity and specificity of FDG PET increased to 94% and 100%, respectively. These findings suggest that FDG PET with the current level of scanner technology is inadequate for evaluation of micrometastatic disease in the axilla. Greco et al (166) reported a similar sensitivity (94%) and specificity (86%) for FDG PET in 167 patients with breast cancer, 72 with axillary nodal involvement; the overall accuracy for nodal staging was 90%. In the largest prospective multicenter study (157) of the use of FDG PET for detection of axillary nodal metastases, a sensitivity and a specificity of 61% and 80%, respectively, were reported in patients who had at least one probably or definitely involved axillary node seen on PET images. The authors of that report also found a high positive predictive value in patients with two or more nodes identified on PET images, but the sensitivity was low (27%). Overall, the results of that study confirmed earlier results showing that FDG PET will frequently fail to depict nodes with micrometastases, and the authors concluded that FDG PET should not be used routinely for axillary lymph node staging. Authors of another study (167), with 165 patients, found a sensitivity and a specificity of 28% and 86%, respectively, for FDG PET in the evaluation of axillary nodes.
There has only been one study of which we are aware in which PET/CT for axillary lymph node staging was evaluated—a small study with 15 patients (168). The authors of that study reported a sensitivity, specificity, and accuracy of 80%, 90%, and 87%, respectively. However, given the combined sensitivity limitations of both PET and CT for detection of micrometastases, it is unlikely, given the current scanner technology, that the combination of the two modalities will overcome their limitations or replace scintigraphy of sentinel lymph nodes (169–173).
In contrast to the limited role FDG PET plays in evaluation of the axilla, it has been shown to be very useful for helping identify unsuspected internal mammary lymph nodes and distant metastases. Avril et al (163) found that FDG PET offered additional information for identifying disease outside the axilla in 12 (29%) of 41 patients. Smith et al (159) and Schirrmeister et al (158) reported unsuspected distant metastatic lesions in 2.6%–4.0% of patients. Other groups have confirmed the ability of PET to demonstrate unsuspected disease or help confirm equivocal lesions seen on anatomic images (156,174–176). In the study by Eubank et al (174), 30% of patients had unsuspected disease in the mediastinum or internal mammary lymph node chain that was only identified by reviewing FDG PET images.
Restaging
It is clear from a number of studies that FDG PET has a very high sensitivity (92%–100%) for the detection of breast cancer recurrence (177–180). However, depending on when PET or PET/CT is performed in the posttherapeutic period, the specificity tends to be lower (72%–82%). In a study by Lonneux et al (181), FDG PET demonstrated recurrence in 31 of 33 patients, compared with eight of 33 for conventional imaging, with bone and internal mammary lymph nodes accounting for the majority of unsuspected lesions. Bender and colleagues (182), in a study with 75 patients, showed a similarly high sensitivity of FDG PET for detection of nodal (97%) and osseous (100%) recurrence, but FDG PET was less sensitive (73%) than CT and MR imaging (93%) for detection of local recurrence. Authors of another study (180) reported a high sensitivity (93%) of FDG PET for detection of recurrence in all patients, but false-positive findings included FDG uptake in muscle, physiologic bowel activity, and FDG uptake in inflammation, most of which could easily be differentiated with combined PET/CT, which would then increase the specificity.
Cook et al (176) compared FDG PET with traditional bone scanning and found that FDG PET was superior with regard to detection of osteolytic metastases, although overlap between the ability of the two modalities to depict different lesions is unlikely to allow FDG PET to replace bone scanning. In a preliminary report (183) on the use of PET/CT in patients suspected of having recurrence on the basis of clinical examination findings or tumor markers, PET/CT demonstrated recurrent lesions in 77% of patients, leading to a change in clinical care in 36%. Another group (184) reported patient-based sensitivity and specificity of 96% and 89%, respectively, which is in the range of most FDG PET sensitivities reported but represents an improvement in specificity over FDG PET alone.
In our experience, PET/CT is often helpful for accurate localization of lesions in patients with breast carcinoma, particularly osseous or soft-tissue metastases, that are subtle on anatomic images or do not have a correlative CT abnormality. In addition, PET/CT helps to differentiate physiologic from pathologic FDG uptake (Fig 13).
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Figure 13a: Restaging in 45-year-old woman with history of right breast carcinoma who had undergone lumpectomy and radiation therapy. Transverse (a) CT and (b) fused PET/CT images show focal abnormality (arrow) just posterior to right brachiocephalic vein. Lesion was not initially seen on a, but b provides exquisite localization and confirms presence of the node.
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Figure 13b: Restaging in 45-year-old woman with history of right breast carcinoma who had undergone lumpectomy and radiation therapy. Transverse (a) CT and (b) fused PET/CT images show focal abnormality (arrow) just posterior to right brachiocephalic vein. Lesion was not initially seen on a, but b provides exquisite localization and confirms presence of the node.
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Response to Therapy
Several studies (185–189) have demonstrated the ability of FDG PET to help predict which patients will respond to therapy which will not by evaluating changes in standardized uptake values. Often with anatomic imaging studies, bulky areas of disease are difficult to evaluate early after therapy. PET/CT scanners combine the strength of FDG PET in helping determine early changes in metabolic activity with the ability to accurately localize areas of persistent disease; they can also assist in depicting areas of persistent uptake for potential biopsy localization.
One of the biggest advantages of combined PET/CT in patients with breast carcinoma is likely to be in radiation therapy evaluation, as described in several reports in patients with various malignancies evaluated with PET/CT for radiation therapy purposes (56,64,65,126,190–198). To minimize overutilization of the modality, however, it will be necessary to have some forethought as to which patients may be candidates for radiation therapy, to ensure that they are evaluated properly on a radiation therapy pallet.
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COLORECTAL CANCER
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Colorectal carcinoma is the third most common malignancy in the United States, with 146 940 new cases diagnosed in 2004. Even though there has been a slight decline in the incidence, colorectal cancer still accounts for approximately 10% of all cancer deaths (n = 56 730) (199).
Initial Diagnosis
Very few studies have evaluated the use of FDG PET and/or PET/CT for screening or initial diagnosis of colorectal carcinoma. Neither is routinely recommended for this purpose. In one study, Chen et al (200) examined PET scans from 3210 asymptomatic patients and found that 20 patients had a premalignant or malignant lesion, most of which were found to be early stage (Dukes C or less) lesions. The current costs of PET and PET/CT make them prohibitive for widespread use as a screening modality.
Staging
Unfortunately, the data to date suggest that PET is not sensitive for detection of colorectal carcinoma regional lymph node involvement, with a sensitivity of only 29% (201). However, the specificity has been reported to be very high (96%), so that the presence of hypermetabolic regional nodes on PET images is worrisome for nodal involvement. If the primary lesion is bulky, the small adjacent lymph nodes may not be resolved as separate structures on PET images (201,202). In contrast, CT can often be helpful in the detection of small lymph nodes adjacent to the primary lesion, although even CT may be unable to depict tiny malignant lymph nodes or micrometastases. Cohade and colleagues (203) compared PET/CT with PET alone and found that PET/CT resulted in a 50% reduction in equivocal or probable lesions and increases in definite characterization and location in 30% and 25% of lesions, respectively.
PET and PET/CT have been very successful in helping identify distant metastases that can have a drastic effect on patient care before surgery. Hepatic metastases are present in approximately 10%–25% of patients. PET and PET/CT will often depict lesions not readily seen on single-phase CT images (Fig 14). FDG PET has been shown to be superior to CT for the identification of hepatic metastases, with a sensitivity and specificity, respectively, of 88% and 100%, compared with 38% and 97% for CT (201). In another study, Lai et al (204) reported that FDG PET demonstrated hepatic lesions in 32% of patients, resulting in a change in care in 29%.
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Figure 14a: Restaging in 56-year-old man with colorectal carcinoma. (a) Transverse CT image shows no abnormality (arrow) even with good portal venous phase contrast material enhancement. (b) Transverse fused PET/CT image shows focal area of intense FDG uptake (arrow) just posterior to a vessel in the area. Three additional lesions in lumbar vertebral body, pericardium, and right hilar area were identified only with PET and were accurately localized with PET/CT.
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Figure 14b: Restaging in 56-year-old man with colorectal carcinoma. (a) Transverse CT image shows no abnormality (arrow) even with good portal venous phase contrast material enhancement. (b) Transverse fused PET/CT image shows focal area of intense FDG uptake (arrow) just posterior to a vessel in the area. Three additional lesions in lumbar vertebral body, pericardium, and right hilar area were identified only with PET and were accurately localized with PET/CT.
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FDG PET has shown limited utility for evaluation of hepatic lesions smaller than 1 cm in diameter, but current technology will likely allow detection of smaller lesions than has been reported in these earlier studies (205,206). We have noted an improved ability to localize FDG-avid lesions to particular hepatic segments, which is helpful both when a correlative lesion is not observed on CT images and for preoperative surgical planning.
Restaging
After surgery and radiation therapy for colorectal cancer, it can be very difficult to differentiate posttreatment changes from recurrent or residual tumor. PET has been shown to be very sensitive and specific for differentiating tumor from treatment changes. In a meta-analysis by Huebner et al (207), PET had an overall sensitivity of 97% and a specificity of 76%, compared with CT (76% and 56%, respectively), for detection of metastases throughout the body and a 95% sensitivity and 97% specificity for detection of local recurrence. There was a corresponding 29% change in patient care.
Differentiation of posttreatment change from recurrent or residual tumor in the presacral area is often particularly challenging for anatomic imaging modalities. PET has been shown to be superior to CT and MR imaging in demonstrating recurrence in this area (208). Schiepers and colleagues (209) demonstrated the importance of PET to help differentiate scar from recurrent tumor: In their study, PET had a sensitivity of 93% and a specificity of 97%, compared with CT (60% and 72%, respectively). PET/CT can often aid in biopsies by providing more exact localization of tumor or, if there are multiple lesions, by directing the biopsy to the lesion that is the most FDG avid (Fig 15).
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Figure 15a: Restaging in 63-year-old man with history of colorectal carcinoma and recent increase in tumor marker levels. (a) Transverse CT image shows two abnormal foci in presacral area, which were worrisome for tumor recurrence (arrow). (b) Transverse fused PET/CT image through this area shows that only one of the two foci on a is FDG avid (arrow). Directed biopsy of this lesion showed recurrent adenocarcinoma. Interestingly, at surgical excision both lesions were positive for tumor.
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Figure 15b: Restaging in 63-year-old man with history of colorectal carcinoma and recent increase in tumor marker levels. (a) Transverse CT image shows two abnormal foci in presacral area, which were worrisome for tumor recurrence (arrow). (b) Transverse fused PET/CT image through this area shows that only one of the two foci on a is FDG avid (arrow). Directed biopsy of this lesion showed recurrent adenocarcinoma. Interestingly, at surgical excision both lesions were positive for tumor.
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A recent study (210) with 76 patients showed PET/CT to be superior to CT for helping establish the presence of intrahepatic recurrence in patients who had undergone partial hepatectomy. The authors of that report also found a 93% sensitivity for PET/CT, compared with 53% with CT, for the evaluation of local recurrence, with a 21% change in therapeutic strategy on the basis of additional PET/CT findings.
PET and PET/CT have also proved to be helpful in patients who have undergone radiofrequency ablation for hepatic metastases (211–217). Typically, serial anatomic imaging was performed in these patients to enable detection of changes over time, whereas metabolic imaging has proved to be helpful in detecting recurrence earlier (Fig 16). Veit et al (211) reported a sensitivity of 65% for both PET and PET/CT, compared with CT alone (44%), in patients who had undergone radiofrequency ablation.
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Figure 16a: Detection of residual or recurrent tumor in 63-year-old man with a history of multiple metastatic liver lesions who had undergone radiofrequency ablation of three hepatic metastases. (a) Transverse CT image shows two low-attenuation lesions in the liver (arrow = posterior lesion). (b) Transverse fused PET/CT image accurately shows residual or recurrent tumor in anterior border of the more posterior lesion (arrow). Anterior lesion appears to have been successfully ablated.
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Figure 16b: Detection of residual or recurrent tumor in 63-year-old man with a history of multiple metastatic liver lesions who had undergone radiofrequency ablation of three hepatic metastases. (a) Transverse CT image shows two low-attenuation lesions in the liver (arrow = posterior lesion). (b) Transverse fused PET/CT image accurately shows residual or recurrent tumor in anterior border of the more posterior lesion (arrow). Anterior lesion appears to have been successfully ablated.
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The main limitations of FDG PET and PET/CT in the pelvis are related to tumor size, FDG avidity, and differential physiologic uptake in structures of the abdominopelvic region, the latter being easily overcome with PET/CT. However, small tumors (<5–10 mm) may not be detected with either modality, with PET being particularly poor at demonstrating early carcinomatosis. Certain tumors, such as mucinous tumors may not be particularly FDG avid, making correlation with CT even more important in these cases (218). After radiation therapy, a period of 2–3 months should be allowed before imaging to reduce the likelihood of false positive studies (219).
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NON-HODGKIN AND HODGKIN LYMPHOMA
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Initial Diagnosis
Lymphoma is subdivided into non-Hodgkin and Hodgkin types. There were 62 250 total combined new cases in 2004, accounting for approximately 8% of all malignancies (199). Although PET can be used to help differentiate benign from malignant adenopathy, there are many causes of FDG-avid benign adenopathy (220–227), as well as occasional low-grade lymphomas, that show little FDG uptake (228).
Staging
Staging of lymphoma is typically based on the Ann Arbor classification, where disease is classified according to location above or below the diaphragm and to nodal versus extranodal involvement. CT is helpful in determining nodal involvement, with higher degrees of confidence as the size increases. However, CT is limited in demonstrating malignant involvement in normal-sized lymph nodes unless necrosis is present. Gallium 67 (67Ga) has also been shown to be helpful in the staging and restaging of nodal disease in patients with lymphoma. In studies (229–231) comparing FDG PET with 67Ga imaging, PET has shown substantially higher site and patient sensitivities (100% vs 71.5% and 100% vs 80.3%, respectively). In addition, PET images revealed higher-stage disease in many patients.
Most cell types in lymphoma are very FDG avid, and the utility of PET is well established for both non-Hodgkin and Hodgkin disease (230,232–236). FDG PET has been helpful in most applications in patients with lymphoma. Staging can be improved in patients who have CT-depicted disease limited to below the diaphragm but who have one or two small nodes above the diaphragm detected with the aid of PET (Fig 17). In comparative studies of PET and CT (232–234,237–249), FDG PET has been shown to be consistently more sensitive and specific than CT for staging in patients with lymphoma, with a sensitivity of 86%–100% for PET and 26%–100% for CT and a specificity of 92%–100% for PET and 50%–100% for CT. There was wide variability in the diagnostic performance of CT in these studies, whereas the PET data were much more consistent and were always superior to the anatomic imaging data. Hong et al (237) compared FDG PET, CT, and 67Ga imaging for staging of lymphoma and found PET to be superior for evaluation of both nodal and extranodal disease.
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Figure 17a: Staging of recently diagnosed non-Hodgkin lymphoma in 44-year-old woman. (a) Coronal PET image shows disease primarily below the diaphragm (arrowhead). (b) Another coronal PET image, however, shows an abnormality above the diaphragm (arrow), and this was confirmed on (c) transverse fused PET/CT image as a small paraesophageal lymph node (arrow). Presence of tumor below and above diaphragm changed the stage and had prognostic implications.
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Figure 17b: Staging of recently diagnosed non-Hodgkin lymphoma in 44-year-old woman. (a) Coronal PET image shows disease primarily below the diaphragm (arrowhead). (b) Another coronal PET image, however, shows an abnormality above the diaphragm (arrow), and this was confirmed on (c) transverse fused PET/CT image as a small paraesophageal lymph node (arrow). Presence of tumor below and above diaphragm changed the stage and had prognostic implications.
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Figure 17c: Staging of recently diagnosed non-Hodgkin lymphoma in 44-year-old woman. (a) Coronal PET image shows disease primarily below the diaphragm (arrowhead). (b) Another coronal PET image, however, shows an abnormality above the diaphragm (arrow), and this was confirmed on (c) transverse fused PET/CT image as a small paraesophageal lymph node (arrow). Presence of tumor below and above diaphragm changed the stage and had prognostic implications.
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Restaging and Response to Therapy
There are generally two ways of evaluating response to therapy: early assessment, after one to three cycles of treatment (235,250–252), and late assessment of the overall response, usually performed approximately 1 month after cessation of chemotherapy. An early assessment of those who respond to therapy is particularly helpful in patients with a malignancy for which there may be multiple potential chemotherapeutic regimens. Early assessment also helps prevent unnecessary side effects from useless regimens and reduces cost by discontinuing expensive therapy in patients who do not respond to treatment.
Zinzani et al (243) evaluated 44 patients and found not only that PET had a very high predictive value for determining residual disease but also that a positive PET imaging study after therapy was a poor prognostic indicator. Most other studies confirm the same, but a negative PET image correlates less well and, therefore, does not completely exclude the possibility of subsequent disease progression. Nonetheless, there is a major advantage to examining early metabolic changes.
Although formal criteria have been developed for size changes seen on CT images, in patients with bulky disease there is a residual fibrotic mass in 40%–85% of lymphoma patients that is easier to assess over time with PET (253–255). A preliminary study (256) to evaluate PET/CT versus CT and PET performed separately in patients with lymphoma showed an incremental improvement, with patient-based sensitivities of 78%, 86%, and 93% and region-based sensitivities of 61%, 78%, and 96% for CT, PET, and PET/CT, respectively. Another study (257) showed PET/CT to be more accurate for staging (93%) than was PET alone (84%), with discordant image interpretation between PET and PET/CT in approximately 10% of patients. In addition, Schaefer et al (258) compared nonenhanced PET/CT with contrast-enhanced CT and found that PET/CT had a sensitivity and specificity, respectively, of 94% and 100%, compared with 88% and 50% for contrast-enhanced CT.
Both FDG PET and PET/CT are extremely helpful in staging, restaging, and evaluating response to therapy in patients with lymphoma. In our own practice, where we have both PET and PET/CT available, one patient population that is often referred for PET only is that of lymphoma patients who have a good response to therapy, are currently asymptomatic, and are being referred for surveillance. This is a large patient population that, given the low index of suspicion for the presence of disease, can be evaluated adequately with PET alone. Questionable lesions could also be further evaluated by acquiring a limited PET/CT imaging study covering the area in question.
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MELANOMA
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Initial Diagnosis
Melanoma is a highly malignant skin cancer with an incidence in the United States in 2004 of approximately 55 100 (199). The primary lesion is almost always diagnosed clinically at physical examination, with the exception of some rare forms such as ocular melanoma. The primary lesions are often seen on FDG PET and PET/CT images, but the modalities are not routinely used to evaluate the T stage of primary melanoma.
Staging
Because of their lower risk of metastatic disease and inability of PET and PET/CT to depict micrometastases, patients with stage I or II (lesion thickness < 1.5 mm) are not routinely imaged. One study (259) in which patients with lower-stage disease were evaluated showed the sensitivity of FDG PET to be only 17% for detection of malignant nodes. Although the authors of that study also reported a high specificity for PET (96%), such patients are more appropriately evaluated with sentinel lymph node sampling, which has a sensitivity and a specificity of 94% and 100%, respectively, in this patient population. Patients with stage III or IV disease are at high risk for metastases, and PET has been shown to be useful in the evaluation of this patient population, with a sensitivity and a specificity, respectively, of 94% and 83%, compared with 55% and 84% for CT (260,261). In a literature review by Schwimmer et al (262), PET was found to have a sensitivity of 92% and a specificity of 90% for the detection of metastatic disease.
Restaging
Patients with stage III or IV disease are also the ones who will be routinely followed up with PET and PET/CT. FDG PET has been shown to be superior to conventional imaging, with a sensitivity and specificity ranging from 85%–92% and 90%–94%, respectively, compared with 57%–81% and 45%–87% for conventional imaging (263,264). We are aware of no larger studies in which the utility or added benefit of PET/CT was evaluated; however, there are many reports of PET/CT aiding in the localization and diagnosis of disease (33,265–267). In our experience, PET/CT can be helpful in further characterization and localization of potential metastases, particularly when subtle soft-tissue lesions may not be easily seen on CT images (Fig 18).
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Figure 18a: Restaging in 40-year-old woman with melanoma and recent abnormality detected on chest radiograph (not shown). (a) Transverse CT image shows subtle area of mild contrast enhancement (arrow) in left gluteal muscle that was not seen prospectively. (b) Transverse fused PET/CT image clearly confirms metastasis (arrow) in gluteal muscle.
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Figure 18b: Restaging in 40-year-old woman with melanoma and recent abnormality detected on chest radiograph (not shown). (a) Transverse CT image shows subtle area of mild contrast enhancement (arrow) in left gluteal muscle that was not seen prospectively. (b) Transverse fused PET/CT image clearly confirms metastasis (arrow) in gluteal muscle.
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SUMMARY
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Many of the studies published over the past few years have demonstrated what was expected intuitively: For many clinical applications, fused PET/CT images consistently outperform CT and PET images acquired separately and viewed together. PET/CT also appears to outperform both CT alone and PET alone. There are still issues related to how the CT portion of a PET/CT examination should be performed, as well as whether intravenous and oral contrast materials are needed, but PET/CT will likely continue to gain in popularity and use in the field of oncology. It offers imaging consolidation, decreased examination time, and increased throughput, as well as superior performance and exquisite localization capabilities.
The main challenge facing oncologic imaging with PET/CT is the limited availability of new tracers to image aspects of malignancy other than glucose utilization. FDG is a nonspecific imaging agent of cancer, although it is useful for whole-body surveys to help stage disease. With a continuing progression toward the development of highly specific molecular probes, the role of the PET/CT technology will increase as the functional images contain fewer and fewer anatomic landmarks.
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ESSENTIALS
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- Some of the most recent technologic developments in PET/CT instrumentation are reviewed, as are the clinical indications for which combined PET/CT has been shown to be more useful than PET and CT performed separately.
- Combined PET/CT imaging facilitates the separation of normal physiologic uptake from pathologic uptake, allows accurate localization of functional abnormalities, and reduces the incidence of false-positive and false-negative imaging studies.
- Many of the studies published over the past few years have demonstrated what was expected intuitively: For many clinical applications, PET/CT images consistently outperform CT and PET images acquired separately and viewed together.
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FOOTNOTES
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Abbreviations: FDG = fluorine 18 fluorodeoxyglucose • SCC = squamous cell carcinoma
2 Current address: Departments of Radiology, Neurology, and Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga. 
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ABSTRACT
INTRODUCTION
