In previous studies, quantitative diffusion-weighted (DW) MRI has shown its potential to differentiate between benign and malignant vertebral body fractures. The diagnostic potential and optimum sequence parameters of diffusion-weighted echo-planar imaging (DW-EPI) sequences, in particular, have been researched [
1–
4] because of the capability of DW-EPI to shorten the acquisition time. However, because of some problems associated with this technique, such as limited spatial resolution, sensitivity to eddy currents and local susceptibility gradients, and chemical-shift artifacts [
5], previous studies revealed contradictory results regarding the diagnostic capability of quantitatively evaluated DW-EPI sequences to differentiate between benign and malignant vertebral body fractures [
1,
4,
6–
9]. Quantitatively evaluated DW fast spin-echo and DW single-shot turbo spin-echo (TSE) sequences [
6,
7,
10,
11] have shown promising results but also a notable overlap between benign and malignant fractures.
The purpose of this study was to determine the optimum combination of b values for calculating the apparent diffusion coefficient (ADC) using a DW single-shot TSE sequence to differentiate acute benign and malignant vertebral body fractures.
Subjects and Methods
Patients
After we obtained approval by the local ethics committee and informed consent, 46 consecutive patients (27 women and 19 men; mean age, 66.6 years; range, 24.7–86.4 years) who were admitted from the emergency department or the orthopedic department with acute benign vertebral body fractures (group 1: 18 women and eight men; mean age, 69 years; range, 31.5–86.2 years) and acute malignant vertebral body fractures (group 2: nine women and 11 men; mean age, 63.4 years; range, 24.7–86.4 years) were included in the study.
We enrolled patients who were over 18 years old with a clinical presentation of back pain for less than 3 months at the level of the vertebral fracture and bone marrow edema on STIR at the fracture site. Pregnancy, contraindications to MRI, diffuse hematologic disorders, contraindications to gadolinium-containing contrast agents, and mental incapacity to voluntarily take part in the study were the exclusion criteria. The patients were assigned to group 1 or group 2 by histology (n = 24), follow-up MRI (n = 11), PET/CT (n = 3), or clinical follow-up including CT after more than 6 months (n = 8).
In group 1, five patients suffered from at least one newly or formerly diagnosed malignant disease (breast cancer, uterine cancer, renal cancer, non-Hodgkin lymphoma); in these and two other patients without known malignant disease, the presence of a malignant fracture was excluded by histology (n = 7). The other patients of this group underwent follow-up MRI (disappearance of edema, no morphologic signs of malignancy in the fractured vertebral body combined with clinical followup) (n = 11) and CT after more than 6 months without morphologic signs of malignancy combined with clinical follow-up (n = 8) to exclude a malignant fracture. In the benign group, one fracture affected the upper thoracic spine (T1–T6), 12 fractures affected the lower thoracic spine (T7–T12), and 14 fractures affected the lumbar spine. In group 2, the primary neoplasms were renal cell carcinoma (n = 1), thyroid carcinoma (n = 1), multiple myeloma (n = 6), breast cancer (n = 5), hypopharyngeal cancer (n = 1), nonseminoma (n = 1), bladder cancer (n = 1), adenocarcinoma (n = 3), and lung cancer (n = 1).
The diagnoses of the malignant origin of the fractures were confirmed by histopathologic examination of specimens obtained during surgery (n = 4), CT-guided biopsy (n = 13), or PET/CT showing a definite pathologic SUV after a time of 7–20 months (n = 3). In the malignant group, two fractures affected the upper thoracic spine (T1–T6), seven fractures affected the lower thoracic spine (T7–T12), and 11 fractures affected the lumbar spine.
MRI
The measurements were performed with a 32-channel 1.5-T MRI scanner (Magnetom Avanto, Siemens Healthcare) using a quadrature spine surface coil. For lesion localization and proper slice positioning, we used a morphologic MRI protocol, which consisted of a T1-weighted (TR/TE, 531/12), STIR (TR/TE, 3790/61; inversion time, 180 ms) and T2-weighted (TR/TE, 4420/118) TSE sequence. Twenty-one sagittal slices with a slice thickness of 3 mm were acquired using a 44 × 44 cm2 FOV and a matrix size of 384 × 384. The total acquisition time for these morphologic images was 6 minutes 30 seconds.
The patients were examined with a fat-saturated DW single-shot TSE sequence (TR/TE, 3000/72; 128 × 92 matrix; flip angle, 180°; bandwidth, 735 Hz/pixel) using b values of 100, 250, 400, and 600 s/mm2. The diffusion weightings were applied in a diagonal direction (gradients in all three dimensions were applied simultaneously). Ten averages were taken to improve the signal-to-noise ratio (SNR) because of the generally low signal intensity of bone marrow. The acquisition time for this DW sequence was 2 minutes 13 seconds.
Postprocessing
Two radiologists with more than 12 and 8 years of experience in musculoskeletal imaging interpreted the images using software developed in-house (PMI 0.4, Platform for Research in Medical Imaging, written in IDL 6.4, ITT Visual Information Solutions). This software was used for image viewing, selection of the ROIs, calculating the different ADC values, and generating the exemplary ADC map (
Fig. 1F). For image evaluation, the readers were blinded for age, sex, and possibly underlying malignant diseases. The fracture with the highest signal intensity on the STIR sequence at the level of back pain was selected, assuming that recent benign fractures would show a stronger edema pattern than older ones [
12] and that recent malignant fractures also show high signal intensity. In patients with multiple fractures, we chose only one acute fracture for statistical reasons, and both readers evaluated the same vertebral body. In group 1, 12 of 26 patients had other fractures (four had one other fracture and eight had two other fractures) that showed lower signal intensity than the fracture chosen. In group 2, six of 20 patients had other fractures (three had one other fracture, one had two other fractures, and two had three other fractures) that were of smaller extent and at a different spinal level of maximum pain than the fracture chosen. In group 2, 17 of 20 patients had other focal bone marrow lesions in nonfractured vertebral bodies.
Each ROI was manually adapted to the area of hyperintense signal intensity on STIR-hypointense signal intensity on T1-weighted images. Each ROI was exactly copied to the DW images and corrected for distortions if necessary (
Fig. 1). For each ROI, all possible combinations of two, three, and four b values were used to calculate the ADC using a least-squares algorithm [
13].
Statistical Evaluation
All analyses were performed using SPSS, version 12, software, and a p value of < 0.05 was defined to indicate statistical significance. Statistical differences were calculated using the Student t test for normally distributed data and the Mann Whitney U test for nonnormally distributed data. Additionally, an ROC analysis was performed and the AUC and the Youden index with the cutoff values for the best sensitivity and specificity were given. The positive (PPV) and negative predictive values (NPV) also were determined.
Results
The ADCs calculated with the combination of b = 100, 250, 400, and 600 s/mm
2 in the same cohort were evaluated as part of a previous study by the same authors [
6]. All other combinations of b values have been exclusively evaluated for this study. The results are summarized in
Tables 1 and
2 and
Figures 2 and
3. All calculated ADCs, except for the combination of b = 400 and 600 s/mm
2, showed statistically significant differences between benign and malignant vertebral body fractures, with benign fractures having higher ADCs than malignant ones. The use of higher b values resulted in lower ADCs than calculated with low b values (e.g., mean ADC
100/250 malignant = 1.67 × 10
−3 mm
2/s and mean ADC
100/250 benign = 2.00 × 10
−3 mm
2/s vs mean ADC400/600 malignant = 1.23 × 10
−3 mm
2/s and mean ADC400/600 benign = 1.16 × 10
−3 mm
2/s). The calculation of the ADCs with three or four higher b values instead of two also decreased the mean ADC (e.g., mean ADC
100/250 malignant = 1.67 × 10
−3 mm
2/s and mean ADC
100/250 benign = 2.00 × 10
−3 mm
2/s vs mean ADC100/250/400 malignant = 1.36 × 10
−3 mm
2/s and mean ADC100/250/400 benign = 1.8 × 10
−3 mm
2/s vs mean ADC100/250/400/600 malignant 1.31 = × 10
−3 mm
2/s and mean ADC100/250/400/600 benign = 1.64 × 10
−3 mm
2/s).
The ROC analysis revealed the highest AUC for the ADCs calculated with b = 100 and 400 s/mm
2 (AUC = 0.85) (
Tables 1 and
2 and
Figs. 2 and
3B) and the second highest AUC for the ADCs calculated with b = 100, 250, and 400 s/mm
2 (AUC = 0.829) (
Tables 1 and
2 and
Figures 2 and
3). The analysis of the Youden index with equal weight given to sensitivity and specificity suggests the use of an ADC calculated with the b values of 100, 250, and 400 s/mm
2 lower than 1.7 × 10
−3 mm
2/s to best diagnose malignancy (sensitivity, 85%; specificity, 84.6%; PPV, 81%; NPV, 88%) (
Tables 1 and
2).
Discussion
DW imaging is based on the Brownian motion of water molecules in the interstitial tissue. The b value determines the duration and strength of diffusion gradients combining several physical factors, specifically the gyromagnetic ratio (γ), the amplitude of the diffusion gradient pulses (
G), the duration of the pulses (δ), and the time between the two diffusion pulses (Δ):
b = γ
2 ×
G2 × δ
2 (Δ − δ / 3) [
14]. The ADC is a quantitative measure of diffusion with regard to several modulating and hindering mechanisms, such as blood flow, restriction in closed spaces, and tortuosity. It can be calculated by collecting images with at least two or more different b values according to the formula:
ADC =
ln [
S2 /
S1] / (
b1 −
b2) where
S1 and
S2 are the signal intensities after application of
b1 and
b2. The ADC can be influenced by other effects on the signal intensity depending on the strength of the applied b values, such as perfusion effects or low SNR [
15–
17].
Although malignant vertebral body fractures are expected to show restricted diffusion (low ADC) due to dense tumor cell packing and restricted extracellular space [
18], acute osteoporotic fractures show an increased diffusion (high ADC) due to increased proton mobility in the bone marrow edema [
3,
4,
9].
Although the underlying water diffusion properties are independent from sequence parameters and scanners, various studies have shown some variability of the measured ADC values of benign osteoporotic or traumatic fractures, which vary from 0.32 to 2.23 × 10
−3 mm
2/s, and of malignant fractures or metastases, which vary from 0.19 to 1.04 × 10
−3 mm
2/s [
17]. These variations may partly be explained by the choice of inappropriate measurement parameters, such as b values that are too low or spatial resolutions that are too high, resulting in low SNRs.
The DW pulse sequence used in this study was a single-shot TSE sequence, which is also known as single-shot fast spin-echo or rapid acquisition with relaxation enhancement sequence; a closely related technique involves the use of DW half-Fourier acquisition single-shot TSE sequences. These spin-echo sequences avoid the frequently gross geometric distortions of single-shot echo-planar imaging (EPI) techniques. The cervical and thoracic spine is often particularly affected by geometric distortions in EPI due to magnetic field inhomogeneity in the area of soft tissue to bone or soft tissue to air interfaces [
19]. However, the spin-echo signal intensity of the single-shot TSE sequence is insensitive to field inhomogeneity at the cost of lower SNR and slightly increased image blurring in structures with short T2. Increasing the number of averages and the receiver bandwidth can mitigate these effects to a certain degree.
There are different physiologic and physical conditions that influence the determination of the ADC. Whereas low b values include more perfusion effects [
15,
16], the use of higher b values decreases the contribution of perfusion and sets the weighting toward diffusion. Relatively high b values greater than approximately 600 s/mm
2, on the other hand, may underestimate diffusion due to signal intensities in the same range as the noise level [
17]. DW images acquired at low b values (< 150 s/mm
2) show good image contrast enhancement that originates from the T2 shine-through effect [
20], whereas the use of high b values is limited by the associated decrease in signal intensity and contrast enhancement [
1].
Malignant fractures are expected to have restricted diffusion capability because of dense cell packing, whereas in benign fractures normal bone marrow and edema are expected to result in an increase in diffusion. The edematous changes in acute benign vertebral body fractures are probably caused by disrupted microvessels and exudation of fluid into the interstitium caused by increased perfusion, whereas in malignant vertebral fractures the size of the interstitial space might be limited because of the densely packed cells presumably associated with a minor degree of perfusion compared with acute benign fractures [
18].
Our results may corroborate these hypotheses. The ADCs in benign fractures were significantly higher than in malignant fractures at most of the possible combinations of b values, which is compatible with the assumption that dense cell packing lowers the ADC. With the use of higher b values, the ADCs in our study also decreased; this can be explained by the lower contribution of perfusion effects and the greater contribution of diffusion at higher b values. The combined use of b = 400 and 600 s/mm2 to calculate the ADC did not show significant differences between benign and malignant fractures and also showed a low AUC (0.659). This may be due to the low SNR of the acquired images because the combination of b = 250, 400, and 600 s/mm2 provides ADCs showing highly significant (p = 0.0062) differences between benign and malignant fractures but also low AUC (0.722). ADCs calculated with low b values (b = 100 and 250 s/mm2) have a lower relative contribution of diffusion (in contrast to perfusion effects) to the signal attenuation, limiting the diagnostic capability in differentiating benign and malignant vertebral fractures, expressed by a low AUC (0.756).
The best diagnostic performance was detected for the ADCs calculated with b = 100 and 400 s/mm
2 and also with b = 100, 250, and 400 s/mm
2. These low-to-intermediate b values may provide a favorable compromise between adequate diffusion weighting and signal intensity. Although two b values (b = 100 and 400 s/mm
2) are sufficient to calculate an ADC, the addition of a third b value (b = 250 s/mm
2) may partially reduce the higher SD introduced by the higher b value (b = 400 s/mm
2). Omitting much higher b values eliminates low-signal-intensity effects. It is also possible that minor perfusion effects, which might occur at low b values, such as b = 100 and 250 s/mm
2, contribute to the ADC at these combinations. Perfusion is known to be different in benign and malignant vertebral body fractures; therefore, it is likely that these perfusion effects at lower b values add to the specificity to discriminate benign from malignant vertebral body fractures [
21–
24]. The highest NPV (88%) with a reasonable balance of sensitivity (85%) and specificity (84.6%) was detected for the combination of b = 100, 250, and 400 s/mm
2, with a cutoff ADC value of ≤ 1.7 ×10
−3 mm
2/s, indicating malignancy. Thus, a fracture detected as benign, is truly benign with a certainty of 88% in that case. Therefore, choosing an adequate combination of b values for calculation of ADCs can improve the diagnostic capability of DW MRI in differentiating acute benign and malignant vertebral fractures.
A possible limitation of our study is the lack of histologic proof of the benign or malignant cause of the vertebral body fracture. For ethical reasons, biopsy or surgical sampling was not possible in all patients. However, clinical and imaging follow-up was performed in all patients to exclude malignancy. Another possible limitation is that investigating different malignant entities might cause a mixed behavior at different diffusion-weightings because of the different tissue composition, perfusion, and size of the extracellular and intracellular spaces, which might influence the signal characteristics of the fractures.