Carolyn C. Meltzer, MD

Several oncologic imaging modalities have evolved significantly since CT was developed in 1973. Although CT provides a noninvasive method for evaluating cancer patients, first-generation scanners were limited in their speed of data acquisition and spatial resolution. Current multislice CT scanners can evaluate a patient completely, with exquisite anatomic detail, in as little as 15 to 30 seconds.

When MR imaging became available in 1983, it made further characterization of suspected malignant lesions possible, often adding complementary information to that found on CT.

Ultrasound, too, offers additional information for evaluation and characterization of several potential malignant lesions. Ultrasound, CT, and MR remain major imaging modalities in clinical oncology, but they generally offer little information regarding the metabolic derangements of tumors. With the use of 2-fluoro-deoxyglucose (FDG) PET imaging, a radioactive glucose analog is injected into patients, and a sensitive coincidence detector system maps the radioactivity.

It has been known since Warburg's observations in the 1930s that many tumors are hypermetabolic compared with surrounding normal tissue, and, therefore, visualization of many tumor types became possible with FDG-PET.1 However, PET imaging provides only limited anatomic detail, and some tumors do not readily take up FDG, making them relatively or absolutely undetectable by FDG-PET (Table 1).

The underlying aberration of cancer is abnormal cellular division and proliferation, which indirectly causes increased metabolic rates for most malignancies. The anatomic findings identified on CT and/or MR in general tend to be later manifestations relative to the functional changes in tumors. FDG-PET can potentially demonstrate metabolic abnormalities earlier in the disease process and enable further characterization of many malignant lesions.

It makes sense, then, that combining an anatomic scanner (CT or MR) with a functional scanner (PET) might be the optimal imaging modality for evaluating oncologic patients. In 1998, the first prototype combined PET/CT scanner was developed at the University of Pittsburgh, and clinical PET/CT scanners became commercially available in 2001.

Although FDG-PET imaging has been in existence since 1976, it wasn't until 1998, when the Centers for Medicare and Medicaid Services announced reimbursement for FDG-PET for several indications (Table 2), that the modality began to be used more frequently. Several valuable clinical applications for FDG- PET can extend to many of the covered indications (Table 3).

- Screening. A few large studies have examined the utility of FDG-PET as a potential oncologic screening tool in asymptomatic patients, with a 2% to 3% detection rate of unsuspected malignancies in the general population.2 The current cost of the procedure outweighs the potential benefits, however, and prohibits its widespread use as a cancer screening modality. False-positive studies are an additional undesirable consequence of screening that also outweighs the potential benefits, due to excessive costs of further evaluation and morbidity from biopsies and other unnecessary invasive diagnostic procedures.

- Carcinoma of unknown primary. Medicare and most third-party payers do not reimburse for FDG-PET imaging of carcinoma of unknown primary (CUP), although up to 5% of all cancer patients receive this diagnosis. FDG-PET has been used to detect and localize primary malignancies, with a detection rate ranging from 43% to 48%.3,4 PET has been shown to influence management in up to 69% of patients for whom it is used to evaluate CUP. Although FDG-PET can be helpful in diagnostically challenging CUP patients, one study reported two-false negative PET exams, reinforcing the fact that absence of an abnormality on FDG-PET does not exclude the presence of disease.

- Differentiating benign from malignant lesions. The most common indication for a PET scan is to evaluate a radiographically indeterminate solitary pulmonary nodule. FDG-PET has been shown in several studies to be more accurate in differentiating benign from malignant nodules larger than 1 cm.5-9 The sensitivity and specificity for all lung nodules is approximately 97% and 78%, respectively, as reported in a meta-analysis evaluating 40 studies and 1474 lung nodules examined with FDG-PET.9

Although FDG-PET can be used to evaluate hepatic, pancreatic, splenic, and other masses or nodules in patients without a pathologic diagnosis of malignancy, a negative PET study in this patient population is often denied by third-party payers. They argue that the test was performed for the evaluation of an unknown primary tumor, currently a nonreimbursable CMS indication.

- Staging following initial diagnosis. FDG-PET has been shown to have a higher sensitivity and at times a higher specificity than CT and/or MR imaging for evaluation of many FDG-avid malignancies, including lung, colorectal, esophageal, and head and neck cancer, as well as lymphoma and melanoma.10-22 The evidence is compelling enough in the staging of these malignancies that the addition of PET imaging has been recommended as the standard of care rather than optional evaluation (Figure 1).23

- Restaging. Several studies have also shown the utility of FDG-PET for many restaging applications in patients with various malignancies. These applications include differentiation of scar from recurrent tumor, evaluation of patients with elevated tumor markers, and surveillance of asymptomatic patients following therapy.24-30 Further, therapy monitoring (Figures 2 and 3) and tracking overall response to therapy are important restaging applications in which evaluation of early metabolic changes following chemotherapy has been shown to be more useful than using traditional anatomic imaging modalities.31-40

The main limitations of PET imaging are the lack of anatomic detail and the inability to evaluate for the presence of microscopic disease and smaller non-FDG-avid tumors. The absolute level of spatial resolution is approximately 5 to 6 mm using current technology.

The remaining limitations of PET imaging are primarily those of FDG, the only FDA-approved oncologic radiotracer. Although many tumor types take up FDG, due to their inherent metabolic upregulation, several malignancies have much less or no FDG uptake. Among these are hepatocellular carcinoma, neuroendocrine tumors, and even some lung cancers, such as bronchoalveolar cell carcinoma among others. (Figure 4).

Several other radiotracers in development focus on examining other cellular processes. One promising radiotracer is 3' deoxy-3'-[F-18] fluorothymidine (FLT), a thymidine analog that reflects cellular proliferation rather than metabolism, although data supporting its routine use are limited.41-46 FLT is also taken up intensely by the liver and bone marrow physiologically, making it an unlikely candidate for single radiotracer evaluation.

CT is the imaging modality most commonly used to evaluate patients with cancer. It is ubiquitous in the medical imaging community and offers superb visualization of internal structures. Current 16 to 64-slice CT scanners provide the ability to obtain true isotropic data sets that permit manipulation of data and visualization of anatomy in axial, coronal, or sagittal planes without loss of anatomic resolution. Volumetric analysis of pulmonary nodules and continued development of CT colonography and other potential screening applications, which have helped reduce the number of more invasive procedures, will undoubtedly play an increasing role.

Using different protocols with intravenous and oral contrast and obtaining data during different phases of contrast enhancement, CT can accurately evaluate many tumors.

MRI is used much less frequently than CT and PET for oncologic applications, with the exception of primary and metastatic brain tumors, for which it is the diagnostic imaging modality of choice. However, MR offers complementary information in many oncologic applications, including liver, renal, and pancreatic mass evaluation. In the case of indeterminate adrenal nodules and masses, MR imaging can help differentiate adrenal adenoma from other, more potentially malignant diagnoses.

The primary limitation of CT is its inability to evaluate the metabolic derangements of tumors. The anatomic detail is much better than can be obtained with PET, but post-treatment changes due to surgery and/or radiation therapy may appear identical to recurrent malignancy on CT. On PET imaging, however, scarring should have no FDG uptake and can easily be differentiated from FDG-avid tumor. In addition, most small malignant lymph nodes, prior to becoming enlarged, appear identical to normal lymph nodes on CT and often on MR. The criteria for differentiating a benign from malignant lymph node, including necrosis, enhancement, and mass effect, are all late manifestations of malignant involvement.

MR imaging has logistical limitations, including the relative inability to scan claustrophobic patients and those with contraindications such as implanted pacemakers and other metallic devices. Otherwise, MR's limitations are similar to those of CT, including the relative inability to determine involvement of normal-sized malignant lymph nodes and to distinguish post-treatment changes from recurrent tumor. Although more functional MR studies and protocols are being developed and performed, MR generally provides limited metabolic/functional information in comparison with PET imaging.

Given the increasing utilization and acceptance of PET imaging in oncology, but also its severe limitations without anatomic correlation, combining PET and CT into a single examination is obviously beneficial. But there are many unexpected synergistic benefits, as well. Performing combined PET/CT rather than PET and CT separately not only consolidates the patient's imaging procedures but also expedites scan times and patient throughput because it avoids a separate PET transmission scan.

The most notable clinical benefit of combined PET/CT is improved lesion localization. Several authors report significant changes and improvement in lesion localization when comparing the PET portion of a PET/CT with fused PET/CT images.47-51

One of the most frustrating aspects of FDG-PET imaging alone is the lack of anatomic landmarks and the inherent uncertainty in localizing areas of FDG accumulation. It is often difficult or impossible to differentiate specific areas of FDG uptake as physiologic or pathologic, given the variable physiologic uptake of FDG in bowel, skeletal muscle, glands, and the genitourinary system.52 By fusing accurately coregistered PET and CT data sets, PET/CT significantly reduces the magnitude of mislocalization of FDG uptake and improves the confidence level of the interpreting physician in precisely localizing lesions.53 Published case reports and series also document how visualizing the fused images helped to resolve potential misinterpretation of benign processes as malignant.54-63

Several reports in the last three years have demonstrated the improved performance and the incremental value of PET/CT over PET, CT, or PET and CT performed separately for staging patients with Hodgkin's and non-Hodgkin's lymphoma and lung and colorectal cancer.64-70

PET/CT has been reported to affect patient management, particularly in radiation therapy evaluation and planning.47,68,71-74 PET/CT scanners were designed to accommodate flat radiation therapy planning pallets. As long as patient movement is minimized between the two scans, accurate coregistration of the two data sets is possible using fusion software, which most radiation therapy planning systems offer. With accurate coregistration, it is possible to view any blended combination of data.

Therapy planning for patients undergoing radiation has traditionally been based solely on anatomic information from a CT scan performed with an approved radiation therapy immobilization pallets. With PET/CT performed with a flat pallets, both the CT and PET data sets can be exported from the acquisition workstation and imported into radiation planning software systems. The patient's radiation therapy plan can then be designed with consideration of not only anatomic information but also metabolic data. This is particularly important for lesions that do not demonstrate a definite anatomic abnormality. When a lesion or the extent of a lesion cannot be adequately identified on the CT portion of the exam, radiation oncologists can integrate the metabolic information from PET for their contouring.

One of the most beneficial applications of combined PET/CT is in restaging patients who have undergone extensive surgery or radiation therapy, both of which tend to distort normal anatomy and cause inflammatory tissue changes. The importance and utility of PET/CT in the restaging of several malignancies, including head and neck, colorectal, thyroid, ovarian cancer, and lymphoma, have also has been reported.64,67,75-77

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3. Mantaka P, Baum RP, Hertel A, et al. PET with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) in patients with cancer of unknown primary (CUP): influence on patients' diagnostic and therapeutic management. Cancer Biother Radiopharm 2003;18(1):47-58.

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Carolyn C. Meltzer, MD

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Anatomic, functional imaging collaborate in cancer detection