FDG PET or PET/CT for Detecting Intramedullary and
Extramedullary Lesions in Multiple Myeloma
A Systematic Review and Meta-analysis
Yu-Yu Lu, MD,* Jin-Hua Chen, PhD,Þ Wan-Yu Lin, MD,*þ Ji-An Liang, MD,þ§ Hsin-Yi Wang, MD,*
Shih-Chuan Tsai, MD,* and Chia-Hung Kao, MDþ||
Aim: The purpose of the current study was to conduct a systematic review and meta-analysis of the published literature to evaluate the diagnostic accu-racy of FDG PET or PET/CT for intramedullary and extramedullary lesions in multiple myeloma.
Methods: The authors conducted a systematic MEDLINE search of published articles. Two reviewers independently assessed the methodological quality of each study. We estimated pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LRj), and summary receiver operating charac-teristic curves in the detection of intramedullary and extramedullary lesions in multiple myeloma.
Results: Fourteen studies with a total of 395 patients met the inclusion crite-ria. The pooled estimates of sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of FDG PET or PET/CT for the detection of extramedullary lesions in multiple myeloma were 96.0% [95% confidence interval (CI), 79.6%Y99.9%], 77.8% (95% CI, 40.0%Y97.2%), 3.28 (95% CI, 1.29Y8.32), and 0.12 (95% CI, 0.03Y0.42), respectively. The pooled estimates of sensitivity, specificity, LR+, and LRj of FDG PET or PET/CT for the detection of intramedullary lesions in multiple myeloma were 61.1% (95% CI, 43.5%Y76.9%), 94.1% (95% CI, 71.3%Y99.9%), 5.73 (95% CI, 1.53Y21.40), and 0.43 (95% CI, 0.28Y0.65), respectively.
Conclusions: Whole-body FDG PET or PET/CT is a valuable imaging tool for the assessment of patients with multiple myeloma, especially for the appraisal of extramedullary involvement.
Key Words: multiple myeloma, FDG PET, PET/CT, systematic review, meta-analysis
(Clin Nucl Med 2012;37: 833Y837)
M
ultiple myeloma (MM) accounts for approximately 10% of all hematological cancers with a peak incidence during the seventh decade.1A proportion of patients with plasma cell myelomahave a different clinical presentation, such as plasmacytoma. Plasma-cytoma can be confined to bone (solitary plasmaPlasma-cytoma of bone) or may occur in extramedullary sites (extramedullary plasmacytoma).2Y5
Approximately 5% to 10% of patients have a solitary bone
plasmacy-toma.6Extramedullary plasmacytoma is even less common than
soli-tary 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 spe-cific criteria that include paraproteinemia, plasma cell infiltration of bone marrow, and osteolytic bone destruction. The presence of extra-medullary involvement and the exact number of lesions in patients with MM have a major impact on prognosis and clinical manage-ment.2,8,9The new Durie/Salmon PLUS staging system9is a refinement
of the original 1975 Durie/Salmon system,10and advanced imaging
studies have been added to the new staging systems to provide more precise staging.9
PET with18F-FDG is a whole-body metabolic imaging
tech-nique that is capable of detecting a wide range of tumors that ex-hibit higher accumulation of FDG than surrounding normal tissues. It has been reported that FDG PET can detect and distinguish between intramedullary and extramedullary lesions11and has been found
use-ful 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 accu-rately 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.
METHODS Literature Search
A comprehensive computer search for relevant articles was conducted using PubMed/MEDLINE and EBM Review search en-gines. 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 refer-ences cited in the retrieved articles.
Data Selection
Studies were eligible for inclusion in the analyses based on the following criteria: (1) they evaluated MM for staging and/or recur-rence, (2) diagnosis was performed by18F-FDG PET or18F-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.
Received for publication December 19, 2011; and revision accepted March 13, 2012. From the *Department of Nuclear Medicine, Taichung Veterans General Hospital; †Biostatistics Center and Graduate Institute of Biostatistics, China Medical University; ‡Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University; and Departments of §Radiation Oncology and ||Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan.
Wan-Yu Lin and Yu-Yu Lu contributed equally to this work.
Conflicts of interest and sources of funding: This study was supported by grants (DMR-100-076 and DMR-100-110) from China Medical University Hospital and the Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH101-TD-B-111-004) as well as the Taiwan Department of Health Cancer Research Center for Excellence (DOH101-TD-C-111-005). The authors declare that they have no conflict of interest.
Reprints: Chia-Hung Kao, MD, Department and PET Center, China Medical University Hospital, No. 2 Yuh-Der Rd, Taichung 404, Taiwan. E-mail: [email protected].
Copyright* 2012 by Lippincott Williams & Wilkins ISSN: 0363-9762/12/3709-0833
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 in-formation 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 be-tween 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 for18F-FDG PET or PET/CT in detecting intramedullary or extramedullary lesions of MM.
Statistical Analysis
Data regarding the diagnostic performance of FDG PET or PET/CT in the detection of intramedullary or extramedullary le-sions 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 LRj (negative likelihood ratio) in intramedullary and extramedullary lesions of MM, respectively. The I2index andW2test would measure the het-erogeneity of the included study. The I2would be less than 53% and P values of W2 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 LRj across studies using the fixed-effects model. For diagnostic tests, the
cor-relations 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 in-cluded studies.13
Likelihood ratios are also metrics that combine sensitivity and specificity in the calculations. The ratio of sensitivity over 1 j specificity is defined as LR+. The ratio of 1 j sensitivity over specificity is defined as LRj. The discrimination ability is better with higher LR+ and lower LRj. In previous articles, a clinically useful test was defined when an LR+ was greater than 5.0 and LRj was less than 0.2.14Analyses were conducted using the free software
Meta-DiSc (version 1.4).15
RESULTS Literature Research
A total of 87 studies that investigated MM using FDG PET or PET/CT were found initially. After reviewing the titles and ab-stracts, 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.16Y18 Three studies were excluded because the results of the
diagnostic performance of FDG PET or PET/CT could not be estimated.19Y21 A total of 395 patients from fourteen eligible
studies8,11,22Y33were analyzed in the systematic review (Fig. 1).
Study Characteristics
The characteristics of the eligible studies are summarized in Table 2. Five of the studies were prospective,23,26,27,29,31and 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,8,11,22Y24,307 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 intrame-dullary lesions,22,31,33 4 studies showed results of the diagnostic
performance for extramedullary lesions,11,28,29,32and the others
de-scribed results of the diagnostic performance for both intramedullary and extramedullary lesions.
Quality Assessment
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.
TABLE 1. Criteria List Used to Assess the Methodological Quality of the Studies
Criteria of Validity Positive Score
Internal validity
Valid reference test Pathology from biopsy or surgery
Blind measurement of FDG PET without knowledge of reference test Blind measurement of reference test
without knowledge of FDG PET
Avoidance of verification bias Assessment by reference test independent of FDG PET results FDG PET interpreted independently
of all clinical information
Mentioned in publication
Prospective study Mentioned in publication
External validity
Spectrum of disease All stage of disease
Demographic information Age and sex information given
Inclusion criteria Mentioned in publication
Exclusion criteria Mentioned in publication
Avoidance of selection bias Consecutive series of patients Standard execution of FDG PET Type of camera, dose FDG, time
interval, reconstruction
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 per-formed independently of FDG PET results. Five studies were pro-spective (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%.
Performance
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 LRj of FDG PET or PET/CT in the detection of extramedullary lesions in MM were 96.0% [95% confidence interval (CI), 79.6%Y99.9%], 77.8% (95% CI, 40.0%Y97.2%), 3.28 (95% CI, 1.29Y8.32), and 0.12 TABLE 2. Clinical Characteristics for Selected Studies
Author Year Design
No. Patients
Sex
(M/F) Age, y PET or PET/CT
Reference
Test Type
Durie et al8 2002 Retrospective 66 39/27 Mean, 63 (range, 43
Y82) PET PA or FU Intra + Extra
Jadvar et al22 2002 Retrospective 6 5/1 Range, 38
Y62 PET (Siemens, Knoxville, Tenn) FU Intra
Schirrmeister et al23 2002 Prospective 43 26/17 Median, 57 (range, 30
Y75) PET (Siemens, CTI, Knoxville, Tenn)
FU Intra + Extra
Hung et al24 2005 Retrospective 12 4/8 Mean, 49 (range, 30
Y74) PET (Siemens) FU Intra + Extra
Bredella et al11 2005 Retrospective 13 10/3 Mean, 54 (range, 41Y79) PET (Siemens, CTI) PA or FU Extra alone
Breyer et al25 2006 Retrospective 16 12/4 Mean, 58 (range, 30
Y69) PET/CT (Siemens or Philips [Cleveland, Ohio])
PA or FU Intra + Extra Zamagni et al26 2007 Prospective 46 30/16 Median, 55 (range, 42
Y65) PET/CT FU Intra + Extra
Nanni et al27 2007 Prospective 10 7/3 Mean, 58 PET/CT (GE Discovery,
Milwaukee, Wis)
FU Intra + Extra
Nanni et al28 2008 Retrospective 14 11/3 Mean, 55 (range, 31
Y66) PET/CT (GE Discovery) FU Extra (Solitary
plasmacytoma of bone)
Salaun et al29 2008 Prospective 24 17/7 Median, 60 (range, 35
Y78) PET/CT PA or FU Extra
Hur et al30 2008 Retrospective 67 15/7 Mean, 59 (range, 48Y77) PET (Philips) PA or FU Intra + Extra
Shortt et al31 2009 Prospective 24 11/13 Mean, 67.1 (range, 44
Y83) PET/CT (Siemens) PA Intra
Kim et al32 2009 Retrospective 17 V V PET (UGM, Philadelphia,
PA) or PET/CT (GE)
PA Extra alone
Elliott et al33 2011 Retrospective 37 19/18 Mean, 60.8
(range, 43.9Y78.9)
PET/CT (GE Discovery) FU Intra
Extra indicates extramedullary; FU, follow-up; Intra, intramedullary; PA, pathology.
TABLE 3. Quality Assessment of the Selected Studies
Study Year IV EV Total IV Score Total EV Score % of Maximum Score
IV1 IV2 IV3 IV4 IV5 IV6 EV1 EV2 EV3 EV4 EV5 EV6
Durie et al8 2002 + j + j j j + + j j + + 2 4 50 Jadvar et al22 2002 j j j j j j + + j j + + 0 4 33 Schirrmeister et al23 2002 j + + j + + + + + j + + 4 5 75 Hung et al24 2005 + + j j + j + + j j + + 3 4 58 Bredella et al11 2005 + j j j j j + + j j + + 1 4 42 Breyer et al25 2006 j j j j j j + + + j + + 0 5 42 Zamagni et al26 2007 j + j j + + + + + j + j 3 4 58 Nanni et al27 2007 j j j j j + j + j j + + 1 3 33 Nanni et al28 2008 + j j j j j + + + j + + 1 5 50 Salaun et al29 2008 + + j j j + + + j j + j 3 3 50 Hur et al30 2008 + j j j + j + + + + + + 2 6 67 Shortt et al31 2009 + j j j j + + + + + + + 2 6 67 Kim et al32 2009 + j j j j j + j j j + + 1 3 33 Elliott et al33 2011 + + j j + j + + + + + j 3 5 67
(95% CI, 0.03Y0.42), respectively. The SROC curves for extra-medullary 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 LRj of FDG PET (PET/CT) in the detection of intramedullary lesions in MM were 61.1% (95% CI, 43.5%Y76.9%), 94.1% (95% CI, 71.3%Y99.9%), 5.73 (95% CI, 1.53Y21.40), and 0.43 (95% CI, 0.28Y0.65), 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 de-tection 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.
DISCUSSION
The use of FDG PET or PET/CT in the assessment of MM continues to be a topic of considerable debate in the literature. How-ever, 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 in-dicates 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 LRj of FDG PET or PET/CT in the detection of extramedullary lesions of MM were 96.0% (95% CI, 79.6%Y99.9%), 77.8% (95% CI, 40.0%Y97.2%), 3.28 (95% CI, 1.29Y8.32), and 0.12 (95% CI, 0.03Y0.42), respectively.
The pooled estimates of sensitivity, specificity, LR+, and LRj of FDG PET (PET/CT) in the detection of intramedullary
lesions of MM were 61.1% (95% CI, 43.5%Y76.9%), 94.1% (95% CI, 71.3%Y99.9%), 5.73 (95% CI, 1.53Y21.40), and 0.43 (95% CI, 0.28Y0.65), respectively. A high LR+ (95.0) is clinically useful for determining a change that indicates a person has a disease. For patients who had negative results, LRj of less than 0.2 can rule out or decrease the probability of disease.14In addition, there was
sig-nificantly higher sensitivity of FDG PET or PET/CT for the detec-tion of extramedullary than for intramedullary lesions (95% CI, 79.6%Y99.9% vs 43.5%Y76.9%). 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 involve-ment could not be clearly separated into individual 2 2 tables. The pooled estimates of sensitivity, specificity, LR+, and LRj of FDG PET or PET/CT for the detection of a mixture of intrame-dullary and extrameintrame-dullary lesions in MM were 86.7% (95% CI, 79.6%Y92.1%), 96.4% (95% CI, 81.7%Y99.9%), 10.8 (95% CI, 3.36Y35.24), and 0.09 (95% CI, 0.01Y0.73), respectively. In gen-eral, 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 al29reported 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 al16showed that FDG PET/CT visualized more focal
lesions than MRI (PG 0.005). MRI performed better than FDG PET/CT in the detection of a diffuse pattern. Breyer et al25showed
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 al31found that
whole body MRI had a higher sensitivity (68% vs 59%) and spec-ificity (83% vs 75%) than those of FDG PET/CT for the assessment of MM. Hur et al30demonstrated that MRI had a higher detection
FIGURE 2. Summary ROC curves of diagnostic performance of
18F-FDG PET or PET/CT in the assessment of extramedullary
lesions of MM. The 3 data points are from the results of these studies of Bredella et al,11Nanni et al,28and Kim et al.32The
area under the symmetric SROC curve is 0.9163, and the Q* index (overall diagnostic accuracy) is 0.8492.
FIGURE 3. Summary ROC curves of diagnostic performance of
18F-FDG PET or PET/CT in the assessment of intramedullary
lesions of MM. The 3 data points are from the results from these studies of Bredella et al,11Jadvar et al,22and Elliott et al.33
The area under the symmetric SROC curve is 0.8602, and the Q* index (overall diagnostic accuracy) is 0.7910.
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 agree-ment with the findings of Shortt et al31and Hur et al.30These 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 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 studies11,22,25,27,32have 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 de-tection 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 ex-cluded the studies, which have the total score for the combined internal and external validity less than 50%, only 1 study28kept in
the detection of extramedullary lesions and 2 studies31,33kept 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%.
CONCLUSIONS
The results of this systematic review and meta-analysis sug-gest that whole-body FDG PET and PET/CT are both valuable im-aging 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 eval-uation of bone marrow involvement.
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