Value of 18F-FDG PET versus iliac biopsy in the initial evaluation of bone marrow infiltration in the case of Hodgkins disease: a meta-analysis

Cheng, Ganga; Alavi, Abassb

Nuclear Medicine Communications:
doi: 10.1097/MNM.0b013e32835afc19
Original Articles

Objective: We carried out a meta-analysis to evaluate the performance of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET and PET/CT against bone marrow biopsy (BMB) in the initial diagnosis of bone marrow infiltration (BMI) in patients with Hodgkin’s disease (HD).

Materials and methods: Retrospective and prospective studies with direct comparison of 18F-FDG PET with BMB in the initial evaluation of BMI in HD were included. Seven eligible studies were included in the meta-analysis comprising a total of 687 patients.

Results: Both 18F-FDG PET and BMB had excellent specificity in detecting BMI. However, 18F-FDG PET had excellent pooled sensitivity (94.5%; 95% confidence interval: 89.0–97.8%) in detecting BMI in the initial staging of HD patients, whereas the pooled sensitivity of iliac BMB was very poor (39.4%; 95% confidence interval: 30.8–48.4%). The diagnostic odds ratio, a measure of the overall diagnostic power of the test, was much higher for PET (pooled value of 1591) than for iliac BMB (pooled value of 137).

Conclusion: 18F-FDG PET significantly outperforms iliac BMB in the detection of BMI in the initial staging of HD patients and therefore should be used as a first-line study. Iliac BMB has low sensitivity and a high rate of false-negative findings. Thus, a negative BMB finding cannot rule out marrow involvement in HD patients on initial staging.

Author Information

aDepartment of Radiology, Philadelphia VA Medical Center

bDepartment of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence to Gang Cheng, MD, PhD, Department of Radiology, Philadelphia VA Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA Tel: +1 215 823 6368; fax: +1 215 823 4312; e-mail:

Received July 17, 2012

Accepted October 3, 2012

Article Outline
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2-Deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET and PET/computed tomography (CT) have been increasingly used in the evaluation of Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL), including for initial staging 1,2 and response assessment 3,4 and during follow-up after complete remission 5. 18F-FDG PET has been shown to be highly accurate in detecting nodal and extranodal lymphomatous lesions 6 and is highly sensitive in most lymphoma subtypes 7. Bone marrow infiltration (BMI) is of special clinical importance in the initial staging of lymphoma and indicates advanced-stage disease. BMI is traditionally evaluated by bone marrow biopsy (BMB), a historically established gold standard procedure performed in the unilateral or bilateral iliac crest anteriorly or posteriorly. Since the 1990s, it has been established that 18F-FDG PET is valuable in the evaluation of bone marrow involvement in lymphoma 8,9, and multiple recent studies have demonstrated that 18F-FDG PET and PET/CT outperform BMB in identifying BMI in lymphoma patients 10–12.

However, several systemic reviews have reported conflicting data on the diagnostic performance of 18F-FDG PET when compared with BMB in this regard. In 2005, Pakos et al. 13 performed a meta-analysis and found limited value for 18F-FDG PET in the evaluation of BMI in lymphoma patients. Similar findings were reported in another meta-analysis of NHL patients by Chen et al. 14. More recently, Wu et al. 15 reviewed the performance of 18F-FDG PET/CT versus MRI in the evaluation of BMI in lymphoma patients and found that 18F-FDG PET/CT had an excellent pooled sensitivity of 91.6% and pooled specificity of 90.3%, outperforming MRI. Unfortunately, a very important clinical question was not addressed in these reviews: How does the performance of 18F-FDG PET or PET/CT compare against BMB, or what is the role of BMB now that 18F-FDG PET/CT is widely available? In this study, we performed a meta-analysis of 18F-FDG PET studies in the initial evaluation of BMI during the initial staging of HD patients in order to address the diagnostic value of 18F-FDG PET when compared with iliac BMB.

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Materials and methods

Selection and eligibility of relevant studies

We considered all studies examining the relative performance of 18F-FDG PET or PET/CT versus blind BMB (performed in iliac crests) for detecting BMI in the initial staging of HD before initiating any form of treatment. Relevant studies published in the English literature were searched with MEDLINE (last update 15 June 2012). All retrospective and prospective studies with direct comparison of PET or PET/CT with BMB were evaluated. The search was conducted using a combination of the following keywords: (a) PET, positron emission tomography, or fluorodeoxyglucose; (b) lymphoma or Hodgkin disease; and (c) bone or bone marrow.

Our selection criteria were as follows:

Only studies with sufficient data to calculate the true-positive (TP: positive findings in patients with BMI), false-positive (FP: positive findings in patients without BMI), true-negative (TN: negative findings in patients without BMI), and false-negative (FN: negative findings in patients with BMI) values for both PET and BMB were included. Studies without sufficient data for BMB were excluded.

Only studies on initial staging of HD were included. Studies were excluded if conducted on patients who had received therapy before BMB or PET. Studies with mixed cases of HD and NHL were also excluded.

Studies performed with old-style PET-alone machines without attenuation correction were excluded.

Studies were excluded if a positive BMB finding was used as the sole criterion for a BMI. All positive BMB findings were regarded as TP in this analysis. In addition, we adopted the definition of a positive BMI on 18F-FDG PET, as in recent literature 10–12 – that is, abnormal 18F-FDG uptake of bone marrow with a corresponding positive BMB finding, positive MRI findings, or positive clinical follow-up (resolution after appropriate therapy).

Studies had to have a sample size of at least five patients, and case reports were not included.

To avoid duplication of information, only studies with the largest sample size were selected whenever reports pertained to overlapping patient populations.

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Data extraction

This analysis combined all data meeting our criteria, regardless of clinical stage, study design (prospective or retrospective), or type of biopsy (unilateral or bilateral iliac crest biopsy). We contacted investigators of eligible studies to provide additional data if any key information relevant to the meta-analysis was missing.

The performance of PET was compared with that of blind BMB performed in the anterior or posterior iliac crest. Thus, a repeat targeted BMB based on positive 18F-FDG PET findings in selected patients did not change the initial iliac BMB results in this analysis (these cases were regarded as FN BMB findings but TP PET findings if the initial iliac BMB was negative and the repeat BMB was positive for BMI in regions with abnormal 18F-FDG uptake).

The following study descriptions were extracted from each eligible report: patient characteristics (range of age, number of cases, and number of benign and malignant lesions), study design (prospective or retrospective), years of patient enrollment, the interval between BMB and PET, type of PET used, and type of BMB (unilateral or bilateral iliac crest). Data on the TP, FP, TN, and FN values of 18F-FDG PET or PET/CT and BMB in the detection of BM infiltration were calculated from the original data as given in the original publications or as directly provided by the authors.

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Statistical analysis

Data were combined quantitatively across all eligible studies for the analysis of the diagnostic performance of 18F-FDG PET or PET/CT and BMB, respectively. From these data, overall values for TP, FP, TN, and FN for PET and BMB were obtained by pooling data sets. The sensitivity (the percentage of TPs among all cases with BMI), specificity (the percentage of TNs among all cases without BMI), and 95% confidence interval (95% CI) were calculated for the combined data by assuming that these results were a simple proportion from a normal distribution.

We constructed summary receiver operating characteristic (SROC) curves for PET and BMB. The SROC curve was plotted with each data point representing a sensitivity/(1−specificity) from a different study. From the SROC curve, the area under the SROC curve and the Q* index were calculated. Q* is the point at which the sensitivity and specificity had an equal value, indicating that the overall diagnostic accuracy was estimated. The positive and negative likelihood ratio (LR+, LR−) and diagnostic odds ratio (DOR) for each study and for pooled data were also obtained. LR+ is defined as the ratio of sensitivity divided by 1−specificity, whereas LR− is defined as the ratio of 1–sensitivity divided by specificity. In general, a good diagnostic test should have LR+above 5 and LR− below 0.2 (a LR of 1 indicates absolutely no discriminating ability for a diagnostic examination); further, a test with a higher value of DOR has a better ability to discriminate between individuals with and without the disease of interest. When at least one sensitivity and specificity value for an individual study was zero, a correction of 0.5 was added to every cell for that study to define the estimators. Statistical analyses were carried out using Meta-Disc version 1.4 (Unit of Clinical Biostatistics, Ramo`n y Cajal Hospital, Madrid, Spain).

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Eligible studies

Our literature search yielded 179 citations. After a review of titles and abstracts, 29 potentially eligible studies remained. After a review of the full article, an additional 23 studies were excluded (Table 1). We contacted Dr Rigacci 38 and clarified BMI findings on PET and on BMB. We also contacted Dr Pelosi 39, who confirmed that data in an earlier publication had been included in the more recent publication 12. Thus, only data from the later publication were included in the analysis. Finally, six eligible nonoverlapping studies were included in this meta-analysis. Individual study characteristics are presented in Table 2. Two of them were prospective studies, whereas the rest were retrospective studies. In all studies, the inclusion and exclusion criteria were described, as well as a valid reference test.

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Data synthesis

The total number of patients included in these studies was 687. Among them, 127 patients had positive BMI on either 18F-FDG PET and/or BMB. The reported incidence of BMI ranged from 6.5 to 25.7% with a pooled incidence of 18.5%. 18F-FDG PET or PET/CT had TP BMI findings in 120 patients, FP findings in three, TN findings in 557, and FN findings in seven. In contrast, BMB had TP BMI findings in 50 patients, TN findings in 560, FN findings in 77, and FP findings in none. The diagnostic performance for each study and pooled data are shown in Table 3.

Both 18F-FDG PET and BMB had excellent specificity in detecting BMI in HD patients. Across all the eligible studies included in this meta-analysis, 18F-FDG PET or PET/CT had specificity rates ranging from 98.4 to 100% with a pooled specificity of 99.5% (95% CI: 98.4–99.9%), in contrast to BMB, which had 100% specificity rates for individual studies and for pooled data. However, 18F-FDG PET or PET/CT had superior sensitivity to BMB, with sensitivity rates ranging from 78.6 to 100% with a pooled sensitivity of 94.5% (95% CI: 89.0–97.8%) for identifying BMI. In contrast, BMB had a pooled sensitivity of only 39.4% (95% CI: 30.8–48.4%) for identifying BMI. The pooled positive predictive value (PPV) and negative predictive value for PET or PET/CT were 97.6 and 98.8%, respectively, and were 100 and 87.9%, respectively, for BMB. The DOR, a measure of the overall diagnostic power of the test, was much higher for PET (pooled value of 1591) than for iliac BMB (pooled value of 137).

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Summary receiver operating characteristic curves

SROC curves for the diagnostic performance of PET (or PET/CT) and BMB are shown in Fig. 1, demonstrating a larger area under the curve for PET (0.996) than for BMB (0.9695). The Q* index, an indicator of overall diagnostic accuracy with equal sensitivity and specificity, shows that 18F-FDG PET or PET/CT would have a sensitivity of 97.61% at the specificity level of 97.61%, whereas BMB would have a sensitivity of 91.91% at a specificity level of 91.91%. The LR+ and LR− for each study and for pooled data are shown in Fig. 2. 18F-FDG PET had a pooled LR+ of 79.65 (95% CI: 35.88–176.83) and a pooled LR− of 0.06 (95% CI: 0.02–0.21). In contrast, BMB had a pooled LR+ of 68.37 (95% CI: 21.61–216.29) and a pooled LR− of 0.54 (95% CI: 0.36–0.81).

The interstudy heterogeneity χ2-test showed no heterogeneity among the included studies with regard to specificity of PET or iliac biopsy but revealed significant heterogeneity of sensitivity results for PET and for iliac biopsy (P<0.01 for both). This heterogeneity is also illustrated in the figure for SROC, which shows substantial scattered distribution of sensitivities of individual studies around the fitted SROC curves. Similarly, the inconsistency (I2) test revealed 0, 62.7, 0, and 84.9% for PET LR+, PET LR−, BMB LR+, and BMB LR−, respectively.

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Although the value of 18F-FDG PET/CT in detecting BMI is being increasingly recognized, there is no consensus regarding the most appropriate time to use BMB as against 18F-FDG PET in the initial assessment of HD patients. Richardson et al. 26 recently assessed the current practice in the UK through a questionnaire and reported that only 50% of responders (among 34 total responses) used 18F-FDG PET/CT as a routine staging tool in HD patients (in limited-stage HD, 70% of them did not use routine 18F-FDG PET/CT), whereas conventional routine BMB was used in 97% of patients in advanced stage of disease and in 30% of limited stage. Findings in this meta-analysis demonstrate the excellent diagnostic value of 18F-FDG PET in identifying BMI during the initial staging of HD, suggesting that the role of iliac BMB for detecting BMI in HD patients should be reevaluated. Both 18F-FDG PET and BMB had similarly excellent specificity for detecting BMI. However, 18F-FDG PET was superior to BMB, with much higher sensitivity: PET had a pooled sensitivity of 94.5% (95% CI: 89.0–97.8%), whereas BMB had a pooled sensitivity of 39.4% (95% CI: 30.8–48.4%). The low sensitivity of iliac BMB with an LR− of 0.5 indicated that BMB could not effectively rule out BMI in HD patients during initial staging.

Our results are different from those of prior meta-analyses 13,14. A review of the studies included in these two prior meta-analyses revealed that several factors might contribute to poor PET performance in these analyses: (a) in many of these studies, PET imaging was performed with no attenuation correction, and PET imaging without attenuation correction is now outdated and no longer used in current practice. (b) Many of these studies had a mixed patient population of post-therapy cases, leading to frequent observation of increased 18F-FDG uptake in nonmalignant cases, decreasing the accuracy of PET imaging in these patients. (c) In some studies, BMB findings were taken as the gold standard to judge the diagnostic performance of PET, and many 18F-FDG-avid PET lesions were regarded as FP on the basis of blind iliac BMB. The diagnostic performance of 18F-FDG PET cannot be accurately evaluated if a positive BMI is based solely on positive BMB findings. Using iliac BMB finding as the sole criterion of BMI will lead to the following conclusions: 18F-FDG PET can never be as good as BMB, and 18F-FDG PET will have high FP results and low PPV. In fact, these studies reported a PPV of 18F-FDG PET as low as 35.7% 41 and 29.7% 34, far below that observed by us and reported by others. In addition, we noticed that neither of these meta-analyses evaluated the diagnostic performance of BMB.

Our knowledge of and experience in PET and PET/CT has increased with their wide application in recent years. It is now well recognized that mild-to-moderate diffuse uptake in the bone marrow does not indicate BMI in most cases, and multifocal uptake in the BM indicates BMI in most cases if not explained by corresponding history (such as fracture or osteomyelitis) 10,11. Multiple studies have provided strong evidence that, in patients with negative iliac BMB, positive 18F-FDG PET findings of BMI are often TP. The iliac crests are commonly found to not be involved even if 18F-FDG PET demonstrates multifocal BMI elsewhere in the skeleton 10,11,37,40. If a repeat BMB is performed at the site with abnormal 18F-FDG activity, it is almost always positive for BMI, demonstrating very high PPV of 18F-FDG PET 11,12,24,36.

It has long been recognized that BMB is associated with a high false-negative rate (FNR) 42. The reported incidence of BMI in lymphoma patients, based on BMB, varies significantly (4–40%), and the significance of BMB is questioned as in some patient populations it had no clear prognostic value 43. In fact, BMB itself proved that it has a high FNR. The unilateral iliac BMB missed 26–30% (and up to 50% in diffuse large cell lymphoma) of cases with BMI in lymphoma patients, based on the findings of bilateral iliac BMB 44,45, whereas the FNR of bilateral iliac BMB remains unknown. In addition, BMB is an invasive procedure and takes 1–2 weeks for a full report. One of the major reasons for the high FNR of the BMB of the iliac crest was sampling errors, because the procedure was performed blindly regardless of whether there was any clinical evidence of tumor involvement in the biopsy region. This selection of the biopsy site was when evaluation of the BMI was difficult on imaging studies. As lymphomas are solid tumors and often have focal or multifocal BMI rather than diffuse distribution in the bone marrow 37,46,47, a FN finding is inevitable if only one or two sites are biopsied blindly. Iliac BMB was the gold standard in detecting BMI, but only when no imaging studies could effectively detect BMI to guide the selection of the biopsy site. This should no longer be the case as 18F-FDG PET/CT is now widely available with high accuracy in detecting BMI in HD patients. The finding that targeted BMB (performed in bone regions with abnormal 18F-FDG activity) had high sensitivity (as well as specificity) in detecting BMI in lymphoma patients 11,12,24,36 indicates that 18F-FDG PET is a valuable imaging modality in guiding the selection of the BMB site.

This meta-analysis has several limitations. First, the overall sample size was limited. Second, the stage of disease was not taken into consideration. Third, there was significant interstudy heterogeneity in the sensitivity data of PET or iliac biopsy. Fourth, this analysis was limited to initial staging of untreated HD patients and may not apply to restaging. FP finding on 18F-FDG PET is likely to be more common after therapy than on initial evaluation, because chemotherapy or radiation therapy makes patients more susceptible to infectious diseases and also because patients treated with G-CSF or GM-CSF often have increased diffuse bone marrow 18F-FDG uptake 32,48,49.

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Our data demonstrate that iliac BMB has low sensitivity and a high rate of FN findings, whereas 18F-FDG PET is superior to BMB in detecting BMI during the initial staging of HD patients. 18F-FDG PET or PET/CT should be performed as a first-line study in the evaluation of BMI, and, if BMB is indicated, the biopsy site should be selected according to abnormal findings on 18F-FDG PET to minimize the number of FN findings on BMB.

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Conflicts of interest

There are no conflicts of interest.

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biopsy; bone marrow infiltration; 18F-FDG PET; Hodgkin’s disease

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