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Originally published as JCO Early Release 10.1200/JCO.2005.01.904 on April 18 2005 © 2005 American Society of Clinical Oncology.
Role of Positron Emission Tomography in Lymphoma
1 Department of Radiology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA Positron emission tomography (PET) scanning, particularly using [18F]fluorodeoxyglucose (FDG), has recently emerged as a powerful functional imaging tool for assessment of patients with Hodgkin's disease and non-Hodgkin's lymphoma (NHL). Numerous investigations have been reported on its use for staging, restaging, and monitoring tumor response of lymphoma, with only a few exploring its value in predicting the tumor's malignancy grade. In this issue of the Journal of Clinical Oncology, Schöder et al1 seek to determine whether the intensity of FDG uptake measured using the standardized uptake value (SUV) could differentiate between indolent and aggressive NHL. The SUV is a semiquantitative measure of the degree of FDG uptake, which may be conceptualized as the ratio between the tumoral concentration of tracer and its concentration in the entire body if the tracer were evenly distributed throughout. Because of its simplicity, this parameter is widely utilized both in the research setting and in clinical practice. In their study of 97 patients with NHL, Schöder et al concluded that the SUV is lower in indolent than in aggressive NHL, that patients with an SUV > 10 have a high likelihood of aggressive NHL, and that this information may be helpful if there is discordance between biopsy and clinical behavior. These findings clearly have implications in treatment planning and prognosis.
While the study by Schöder et al is the largest to date to attempt to distinguish between indolent and aggressive NHLs based on the SUV, the findings are not very different from those of previously reported smaller studies.2-4 Similar to those previous studies, a considerable overlap in the SUVs was found between indolent and aggressive NHL, with a relatively wide range of SUVs observed even within the same histologic subtype.1-4 This variability could have been even greater had the authors determined the SUVs for all well-delineated tumor lesions in each patient rather than only for the most intense lesion because of the known intrapatient variability in SUV in patients with NHL and other cancer types. Despite this overlap, two conclusions may be drawn reasonably from the data. First, an SUV The moderate sensitivity and specificity of the cutoff SUV of 10 needs to be further evaluated in light of the fact that this value was derived post hoc, potentially resulting in an overestimation of its diagnostic accuracy. However, the findings in the 22 patients in whom the biopsy was taken from a site other than that with the most intense FDG uptake could serve as an initial test for the performance of this cutoff in an independent, albeit small, cohort of patients. Of these 22 patients, 8 (36%) had discordant classifications (ie, indolent or aggressive) between the SUV approach and histopathology, of which 6 (27%) with aggressive histology were misclassified as indolent and 2 (9%) with indolent histology were misclassified as aggressive. There was apparently no indication that the former patients, representing about half of those with aggressive lymphoma, had a less aggressive clinical course compared with those with a SUV of > 10 or 15. The authors' statement that the two misclassified patients with indolent histology may have had aggressive lymphoma at the site of their most intense lesion is highly speculative; no data on their clinical course were provided. The findings in the eight patients with transformed lymphoma further illustrate the practical limitations of the FDG-based SUV approach. Three (38%) of these eight patients had SUVs of < 10 and, here again, there was no evidence of a less aggressive clinical course compared with those with higher SUVs. In aggregate, the results suggest that the FDG-based SUV approach has limited predictive value inside the gray zone between the SUVs of 6 and 13 and that the cutoff SUV of 10 should be treated with extreme caution. Schöder et al are therefore correct when they state that biopsy remains the standard procedure for establishing an unequivocal diagnosis in lymphoma patients and that the primary use of the SUV in this setting will be in those patients in whom biopsies from easily accessible sites are inconsistent with the clinical course of disease. Nevertheless, it is valid to ask whether the information provided in their report can be used to grade NHL in situations in which biopsies cannot be obtained due to inaccessibility or comorbidities.
FDG PET scanning in such circumstances appears justified, and it is reasonable to assume that a SUV One of these approaches may be the determination of the net rate of influx or utilization constant of FDG (Ki), which represents the rate of FDG uptake into the irreversible compartment of phosphorylated and metabolically trapped FDG. This measure is often used as a surrogate for the glucose utilization rate (MRglu) and may be preferable to the latter because of its independence from the lumped constant (LC), which accounts for the differences in transport and phosphorylation of glucose and FDG.5 Estimates of the LC are unavailable for NHLs; the LC is set to 1 by convenience, which may not be valid for many tumors and, consequently, could introduce an important source of error when measuring MRglu. Since the LC is not required to compute the Ki, no assumptions regarding the LC need to be made when determining Ki, thereby eliminating this potential source of error. While Ki is generally highly correlated with the SUV, it is not synonymous with it, and previous studies have shown that Ki can better distinguish between indolent and aggressive lymphoma than is possible using the SUV.2 Rodriguez et al2 showed a much greater difference in the Ki than in the SUV values between aggressive and indolent lymphomas (11- v two-fold higher mean values, respectively, for aggressive v indolent NHL) and, more importantly, lack of overlap in Kis between aggressive and indolent NHL in contrast to considerable overlap in SUVs. A careful examination of the results reported by these investigators indicates that indolent lymphomas apparently exhibit substantially greater increases in SUV than in Ki.2 This finding may be explained by enhanced tumoral cell accumulation of nonphosphorylated FDG (captured in the SUV measure) due to increased glucose transporter activity without a proportional increase in glucose phosphorylation, and, consequently Ki. While the Ki method may be more accurate than the SUV method with FDG PET, it is somewhat cumbersome because of the requirement for dynamic scanning and blood sampling not needed for SUV computation and is, therefore, less practical in the clinical setting. The second, more attractive, approach is the use of in vivo markers of the tumor's proliferative activity, the presumed true measure of its malignancy grade, that are superior to FDG. This approach is based on the fact that lymphomas' proliferative activity and glucose utilization or metabolism are only moderately correlated.3,6,7 This imperfect relationship likely represents an important source of overlap in SUV, but also in Ki between aggressive and indolent disease, as suggested by the report by Leskinen-Kallio et al4 One example of this approach is the use of fluorothymidine (FLT), a reportedly superior marker of tumor cell proliferation compared to FDG.8-10 Using this tracer, Buck et al10 demonstrated excellent separation between aggressive and indolent lymphomas with high correlation observed between the FLT SUVs and tumor proliferative activity. The use of FLT might, therefore, obviate the need for the quantitative or kinetic methods potentially required when FDG is used for grading NHL. In fact, lymphoma grading could prove to be the predominant indication in lymphoma PET imaging, where FLT exhibits a distinct advantage over FDG. However, this indication is likely to have only a limited role in PET use in lymphoma compared with the other indications of staging and restaging and, more recently, monitoring tumor response. For these indications, FDG PET has proven highly valuable and, generally, remarkably accurate. While a thorough appraisal of the different FDG PET indications in lymphoma is beyond the scope of this editorial, the most important contributions of FDG PET in assessment of lymphoma patients may be summarized in a few points. First, in the staging of lymphoma, PET can provide complementary information to conventional procedures such as computed tomography (CT) and bone marrow biopsy, with potential modification of stage (usually upstaging) and impact on management.11-13 There are data that suggest that the number of patients for whom PET alters stage sufficiently to alter therapy is small. In the absence of modification in stage, the often-reported PET demonstration of a greater number of disease sites than is possible with conventional methods could, in certain circumstances, provide important prognostic information. This information could potentially be used to alter the treatment strategy in these patients.14 Second, in restaging of lymphoma, PET is able to distinguish between viable tumor and necrosis or fibrosis in the residual mass(es) often present following treatment without any other clinical or biochemical evidence of disease.15-18 This use is probably the most important, especially in aggressive NHL and Hodgkin’s lymphoma. Conventional imaging modalities are generally unable to differentiate between tumor and necrotic or fibrotic tissue in such masses because of their reliance on morphologic features that are usually indistinguishable between these tissues. False-positive findings at the site of residual masses may be seen, however, due to rebound thymic hyperplasia or post-therapy inflammatory changes, with the latter apparently substantially more frequent following radiation than after chemotherapy or chemoimmunotherapy. False-positive findings outside the site of residual masses may be caused by rebound thymic hyperplasia, or infectious or inflammatory processes including sarcoid. The diffusely increased bone marrow uptake often observed after treatment or administration of growth factor is usually due to bone marrow hyperproliferation and should not be misinterpreted as lymphoma. Primarily because of the superior differentiation between viable tumor and fibrosis in residual masses, our group reports, also in this issue of the Journal,18 that PET performed at the conclusion of treatment of patients with aggressive NHL provided a more accurate prediction of prognosis and more accurate response classifications compared with CT-based assessment. Another contribution of restaging PET is the determination of true extent of lymphoma recurrence suspected by clinical/biochemical or radiographic evaluation. Third, the role of PET scanning for post-therapy surveillance without clinical, biochemical, or radiographic evidence of disease remains controversial, primarily because of the potential for a disproportionate fraction of false-positive findings, potentially resulting in increased cost without proven benefit from earlier PET detection of disease compared with standard surveillance methods.19 Large prospective studies are, therefore, needed to determine whether routine surveillance by PET is cost effective and results in meaningful changes in patient management and/or outcome. Fourth, the role of PET for monitoring response to treatment, defined as PET scanning during rather than at the end of the planned course of therapy, is evolving. The purpose in this setting is to provide an early and yet accurate assessment of response to multicourse treatment with the ultimate goal of tailoring therapy according to the information provided by the scan. Several studies have demonstrated a correlation between a rapid decline or "normalization" of FDG uptake or SUV as early as after one or a few (2 to 4) cycles of chemo- or chemoimmunotherapy and patient outcome in these studies.20-22 For example, in a study of 70 patients with aggressive NHL who underwent FDG PET scanning after 3 or 4 cycles of first-line chemotherapy, Spaepen et al22 showed that none of the 33 patients with a positive scan achieved a durable complete response (CR), whereas 31of 37 patients with a negative scan remained in CR with a median follow-up of 1,107 days. However, no published reports have yet clearly demonstrated that the PET results actually can be used to alter treatment with an improvement in outcome; early PET scanning appears to be currently performed primarily because of the prognostic information provided.20-22 The role of PET for monitoring tumor response is likely to dramatically increase once clinical trials demonstrate that the information provided by PET impacts on patient management or ultimate patient outcome. Finally, it is impossible to discuss the role of PET in lymphoma without addressing the potential impact of the increasingly more widely used PET/CT systems, which combine a PET and a CT scanner in a single instrument. With PET/CT, the functional PET images are coregistered with the anatomic CT images obtained by the almost–simultaneously acquired CT scan. This approach can result in a significant improvement in the diagnostic accuracy of PET, principally because the more accurate anatomic localization of the PET findings by coregistered CT leads to fewer false-positive PET interpretations due to interpatient variability in physiologic FDG uptake. A recently reported study in the staging and restaging of 73 lymphoma patients showed that PET/CT was superior to PET alone with reported accuracies of 93% and 83%, respectively (P = .03).23 Others have shown a similar accuracy for PET/CT and PET interpreted in visual correlation with contrast-enhanced CT, although the CT scan performed as part of a PET/CT was acquired without the use of intravenous contrast.24 It has, therefore, been suggested that PET/CT may obviate the need for intravenous contrast used in conjunction with dedicated CT imaging of lymphoma, but this must first be confirmed in prospective clinical trials including larger number of patients before definite conclusions are made. Irrespective of the findings of such trials, it is likely that PET/CT will emerge as the pre-eminent tool in lymphoma imaging enabling an integrated functional-anatomic tumor assessment with a favorable impact on patient management and, possibly, outcome. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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13 in the most intense lesion indicates a high likelihood of aggressive histology, while an SUV of 
6 is very likely associated with indolent histology. Second, these upper and lower cutoff SUVs provide relatively high accuracy in grading NHL in only approximately 55% of patients, because only approximately 58% of patients with biopsy-proven aggressive histology had an SUV 
