Multiple myeloma (MM) accounts for approximately 10% of all hematological cancers with a peak incidence during the seventh decade.1 A proportion of patients with plasma cell myeloma have a different clinical presentation, such as plasmacytoma. Plasmacytoma can be confined to bone (solitary plasmacytoma of bone) or may occur in extramedullary sites (extramedullary plasmacytoma).2–5 Approximately 5% to 10% of patients have a solitary bone plasmacytoma.6 Extramedullary plasmacytoma is even less common than solitary bone plasmacytoma. Extramedullary plasmacytoma represents approximately 3% of all plasma cell neoplasms.2,6,7 The clinical manifestation of MM results from increasing tumor burden in bones, bone marrow, and extraosseous sites, as well as production of excess monoclonal immunoglobulins. The diagnosis of MM is based on specific criteria that include paraproteinemia, plasma cell infiltration of bone marrow, and osteolytic bone destruction. The presence of extramedullary involvement and the exact number of lesions in patients with MM have a major impact on prognosis and clinical management.2,8,9 The new Durie/Salmon PLUS staging system9 is a refinement of the original 1975 Durie/Salmon system,10 and advanced imaging studies have been added to the new staging systems to provide more precise staging.9
PET with 18F-FDG is a whole-body metabolic imaging technique that is capable of detecting a wide range of tumors that exhibit higher accumulation of FDG than surrounding normal tissues. It has been reported that FDG PET can detect and distinguish between intramedullary and extramedullary lesions11 and has been found useful for improving staging accuracy.8
Despite the increasing number of publications concerning FDG PET in the assessment of MM, patient population, study design, and results vary widely among studies, making it difficult to accurately assess the diagnostic value of FDG PET and PET/CT. In addition, differences between FDG PET and PET/CT in their ability to accurately detect intramedullary lesions and extramedullary involvement have not been clearly delineated. The purpose of the present study was to evaluate the diagnostic accuracy of FDG PET in MM by conducting a meta-analysis of the published literature.
A comprehensive computer search for relevant articles was conducted using PubMed/MEDLINE and EBM Review search engines. The search included combinations of the following terms: (1) PET, positron emission tomography; (2) FDG, fluorodeoxyglucose; (3) multiple myeloma. Searches were limited to studies on human subjects. Although no language restrictions were used initially, the full-text review and final analysis were limited to articles published in English. Additional studies were manually searched using the references cited in the retrieved articles.
Studies were eligible for inclusion in the analyses based on the following criteria: (1) they evaluated MM for staging and/or recurrence, (2) diagnosis was performed by 18F-FDG PET or 18F-FDG PET/CT, and (3) 2 × 2 tables could be derived from the provided data. Abstracts presented at congresses, unpublished data, case reports, meta-analyses, reviews, editorials, and comments were excluded. To avoid missing potentially useful articles for the present meta-analysis, the abstracts were double-checked by at least 2 authors to determine whether the reports fitted the inclusion criteria for this study.
Quality Assessment and Data Extraction
Two reviewers independently assessed the methodological quality of the eligible studies. The criteria list recommended by the Cochrane Methods Working Group on Systematic Review of Screening and Diagnostic Tests was used modified by Chen et al.12 Some items on the list were modified for this specific review. The complete criteria list used is presented in Table 1. Internal validity criteria (IV) were scored as “positive” (adequate methods) or “negative” (inadequate methods, potential bias, or insufficient information had been provided on a specific item). External validity criteria (EV) were assessed to evaluate generalizability. Standard performance of FDG PET or PET/CT was scored positive when the type of PET or PET/CT camera, the dose of FDG, the time between injection and scanning, and the method of reconstruction were described. The criteria for external validity were scored positive if sufficient information was provided to judge the generalizability of findings. Disagreements were resolved by consensus. Quality scores were expressed as a percentage of the maximum score. Subtotals were calculated for internal (maximum, 6) and external (maximum, 6) validity separately.
For each report, we recorded the number of true-positive, false-positive, true-negative, and false-negative findings for 18F-FDG PET or PET/CT in detecting intramedullary or extramedullary lesions of MM.
Data regarding the diagnostic performance of FDG PET or PET/CT in the detection of intramedullary or extramedullary lesions of MM were combined quantitatively across eligible studies. We gathered PET and PET/CT data to estimate the pooled sensitivities, specificities, LR+ (positive likelihood ratio), and LR− (negative likelihood ratio) in intramedullary and extramedullary lesions of MM, respectively. The I 2 index and χ2 test would measure the heterogeneity of the included study. The I 2 would be less than 53% and P values of χ2 test were not significant. We used the fixed-effect model to combine the pooled estimates. The steps were as follows. First, we combined sensitivities and specificities independently across studies. Second, we estimated the weighted LR+ and LR− across studies using the fixed-effects model. For diagnostic tests, the correlations between sensitivity and specificity did not exist. We showed the summary receiver operating characteristic (SROC) curve, which was the symmetrical by Mantel-Haenszel method. The SROC curve shows the trade-off between sensitivity and specificity across the included studies.13
Likelihood ratios are also metrics that combine sensitivity and specificity in the calculations. The ratio of sensitivity over 1 − specificity is defined as LR+. The ratio of 1 − sensitivity over specificity is defined as LR−. The discrimination ability is better with higher LR+ and lower LR−. In previous articles, a clinically useful test was defined when an LR+ was greater than 5.0 and LR− was less than 0.2.14 Analyses were conducted using the free software Meta-DiSc (version 1.4).15
A total of 87 studies that investigated MM using FDG PET or PET/CT were found initially. After reviewing the titles and abstracts, 67 studies were excluded based on the criteria listed in the Data Selection subsection of the Materials and Methods.
We screened the full text of 20 articles. Three studies were excluded owing to insufficient information to construct a 2 × 2 table.16–18 Three studies were excluded because the results of the diagnostic performance of FDG PET or PET/CT could not be estimated.19–21 A total of 395 patients from fourteen eligible studies8,11,22–33 were analyzed in the systematic review (Fig. 1).
The characteristics of the eligible studies are summarized in Table 2. Five of the studies were prospective,23,26,27,29,31 and the others were retrospective. Ten of the studies that provided results of diagnostic performance were patient based and the others were lesion based.24,25,29,30 Six of the studies were performed by FDG PET scan,8,11,22–24,30 7 studies were performed by FDG PET/CT scan, and the other was performed by FDG PET or PET/CT scan. Three of the studies provided results of the diagnostic performance for intramedullary lesions,22,31,33 4 studies showed results of the diagnostic performance for extramedullary lesions,11,28,29,32 and the others described results of the diagnostic performance for both intramedullary and extramedullary lesions.
Methodological quality was assessed by 12 items for each of the 14 selected studies. The scores for internal and external validity of the 14 selected studies are presented in Table 3.
Nine studies had a valid reference test (IV1). The readers were blinded to the results of the reference standard in 5 of the selected studies (IV2). All studies had verification bias (IV4) because patients were selected for assessment by the reference test but this not performed independently of FDG PET results. Five studies were prospective (IV6), and in the other 9 studies, patients were enrolled in the studies consecutively (EV5).
In 13 of the 14 studies, all staging of disease was included (EV1). In 7 studies, the inclusion criteria (EV3) were described, and in 3 studies, the exclusion criteria (EV4) were described. The type of camera, the FDG dosage, the uptake period, the time interval, and reconstruction were reported in 11 of the studies (EV6). The total score for the combined internal and external validity, expressed as a fraction of the maximum score, ranged from 33% to 75%.
The diagnostic performance between PET and PET/CT for MM was not significantly different (P = 0.7458) in meta-regression. The pooled estimated results of FDG PET or PET/CT in the detection of intramedullary and extramedullary lesions in MM were patient based. The pooled estimates of sensitivity, specificity, LR+, and LR− of FDG PET or PET/CT in the detection of extramedullary lesions in MM were 96.0% [95% confidence interval (CI), 79.6%–99.9%], 77.8% (95% CI, 40.0%–97.2%), 3.28 (95% CI, 1.29–8.32), and 0.12 (95% CI, 0.03–0.42), respectively. The SROC curves for extramedullary lesions in MM are presented in Figure 2. The Q* index presents maximum joint sensitivity and specificity, calculated as a global measure of diagnostic accuracy. The Q* index was 0.84 for FDG PET or PET/CT in extramedullary lesions in MM.
The pooled estimates of sensitivity, specificity, LR+, and LR− of FDG PET (PET/CT) in the detection of intramedullary lesions in MM were 61.1% (95% CI, 43.5%–76.9%), 94.1% (95% CI, 71.3%–99.9%), 5.73 (95% CI, 1.53–21.40), and 0.43 (95% CI, 0.28–0.65), respectively. The SROC curves for intramedullary lesions in MM are presented in Figure 3. The Q* index was 0.79 for FDG PET or PET/CT for intramedullary lesions in MM.
The diagnostic performances in the 4 studies that analyzed lesion-based data could not be assessed by meta-analysis because the numbers of true-negative results were not provided. In the other 4 reports, the numbers of true-positive, false-positive, true-negative, and false-negative findings between FDG PET and PET/CT for detection of intramedullary and extramedullary lesions could not be clearly separated into individual 2 × 2 tables. Therefore, the data from these studies could not be pooled into individual results for intramedullary or extramedullary lesions.
The use of FDG PET or PET/CT in the assessment of MM continues to be a topic of considerable debate in the literature. However, to date, FDG PET and PET/CT have not been compared with regard to diagnostic accuracy of MM. In our meta-analysis study, the differences in diagnostic performances between FDG PET and PET/CT for MM were not significantly different (P = 0.7458). This result indicates that neither FDG PET nor PET/CT was a primary factor in the heterogeneity found among studies.
The pooled estimates of sensitivity, specificity, LR+, and LR− of FDG PET or PET/CT in the detection of extramedullary lesions of MM were 96.0% (95% CI, 79.6%–99.9%), 77.8% (95% CI, 40.0%–97.2%), 3.28 (95% CI, 1.29–8.32), and 0.12 (95% CI, 0.03–0.42), respectively.
The pooled estimates of sensitivity, specificity, LR+, and LR− of FDG PET (PET/CT) in the detection of intramedullary lesions of MM were 61.1% (95% CI, 43.5%–76.9%), 94.1% (95% CI, 71.3%–99.9%), 5.73 (95% CI, 1.53–21.40), and 0.43 (95% CI, 0.28–0.65), respectively. A high LR+ (>5.0) is clinically useful for determining a change that indicates a person has a disease. For patients who had negative results, LR− of less than 0.2 can rule out or decrease the probability of disease.14 In addition, there was significantly higher sensitivity of FDG PET or PET/CT for the detection of extramedullary than for intramedullary lesions (95% CI, 79.6%–99.9% vs 43.5%–76.9%). The results of our meta-analysis study suggest that both FDG PET and PET/CT can each provide a good diagnostic performance in the evaluation of MM, especially for extramedullary involvement.
In 4 studies, the diagnostic performances of FDG PET and PET/CT for intramedullary lesions and extramedullary involvement could not be clearly separated into individual 2 × 2 tables. The pooled estimates of sensitivity, specificity, LR+, and LR− of FDG PET or PET/CT for the detection of a mixture of intramedullary and extramedullary lesions in MM were 86.7% (95% CI, 79.6%–92.1%), 96.4% (95% CI, 81.7%–99.9%), 10.8 (95% CI, 3.36–35.24), and 0.09 (95% CI, 0.01–0.73), respectively. In general, the results indicated that FDG PET and PET/CT had a good diagnostic accuracy for the detection of MM.
Six studies compared the diagnostic performances of FDG PET with those of PET/CT with MRI for the detection of MM. Salaun et al29 reported that the performance of FDG PET/CT seemed to be equivalent to that of MRI in spine and pelvic bone. However, MRI missed 18 lesions located outside the areas covered by MRI. They suggested that FDG PET/CT provides additional information for the assessment of MM in areas not covered by MRI.
Fonti et al16 showed that FDG PET/CT visualized more focal lesions than MRI (P < 0.005). MRI performed better than FDG PET/CT in the detection of a diffuse pattern. Breyer et al25 showed that FDG PET/CT was superior to MRI in 7 of 16 patients, and that MRI was superior to FDG PET/CT in 4 of 16 patients, of whom 4 had diffuse bone marrow involvement. Shortt et al31 found that whole body MRI had a higher sensitivity (68% vs 59%) and specificity (83% vs 75%) than those of FDG PET/CT for the assessment of MM. Hur et al30 demonstrated that MRI had a higher detection rate of bone lesions (92% vs 80%) than that of FDG PET. Zamagni et al26 showed MRI was superior to FDG PET/CT in 14 of 46 patients, of whom 10 had a diffuse pattern and 4 had a focal pattern of bone marrow involvement on MRI, which was in agreement with the findings of Shortt et al31 and Hur et al.30 These results indicated that FDG PET or PET/CT can contribute to an accurate whole-body evaluation in patients with MM, whereas MRI is better suited to the evaluation of bone marrow involvement.
There were some potential limitations in this study. First, the clinical heterogeneity may affect the generalizability of the results. Second, it was not possible to detect precisely all lesions in patients with MM (the number of true-negatives was not available), and therefore, the pooled meta-analysis for studies with lesion-based data could not be calculated. Third, 4 studies had results comprising a mixture of intramedullary and extramedullary lesions. Thus, we could not determine the number of true-positive, false-positive, true-negative, and false-negative findings based on the type of lesion, that is, intramedullary or extramedullary. The data could therefore not be pooled into individual intramedullary or extramedullary results. Fourth, pathology findings were available for some lesions, whereas results for other lesions depended on the clinical follow-up, which may have involved a variety of imaging modalities and clinical examinations. Finally, 5 studies11,22,25,27,32 have the total score for the combined internal and external validity less than 50%. In our current meta-analysis, the P value of heterogeneity test in the detection of extramedullary or intramedullary lesions was larger than 0.1 and the number of patients conducted into the individual extramedullary and intramedullary group was not large. If we excluded the studies, which have the total score for the combined internal and external validity less than 50%, only 1 study28 kept in the detection of extramedullary lesions and 2 studies31,33 kept in the detection of intramedullary lesions. The outputs were not very different from meta-analysis results. Therefore, we did not present the data after excluding these 5 studies, which have the total score for the combined internal and external validity less than 50%.
The results of this systematic review and meta-analysis suggest that whole-body FDG PET and PET/CT are both valuable imaging tools for the assessment of patients with MM, especially for the appraisal of extramedullary involvement. The use of FDG PET (PET/CT) with MRI provides complementary information for evaluation of bone marrow involvement.
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