Introduction
Prostate cancer (PCa) is the most prevalent malignant tumour among men and the second leading cause of cancer-related deaths following lung or bronchus cancer. The growing elderly population has led to the highest increase in the number of estimated new PCa cases [
1].
In men with an elevated level of serum prostate-specific antigen (PSA), the diagnosis of PCa before prostatectomy is confirmed histologically by performing a transrectal ultrasound (TRUS)-guided biopsy. However, the high false-negative rate of TRUS-guided biopsy is thought to be unacceptable [
2], and the poor tolerance of patients to the invasive procedures is another challenge [
3]. Therefore, a non-invasive method to diagnose prostate cancer with high accuracy is required.
Various magnetic resonance methods have been investigated for the detection of PCa. In addition to conventional anatomic T2-weighted imaging (T2WI), functional MR techniques such as diffusion-weighted imaging (DWI), dynamic contrast-enhanced imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS) have shown promise in the improvement of non-invasive detection of PCa [
4‐
6]. In particular, DWI is an MR-based technique that probes the function of tissues. It is sensitive to thermally driven molecular water motion, which in vivo is impeded by cellular packing, intracellular elements, membranes and macromolecules. Reduced diffusion of water has been attributed to the increased cellularity of malignant lesion, with reduction of the extracellular space and restriction of the motion of extracellular water [
7,
8]. This approach was initially applied to neurologic disorders [
9]. Recently, numerous studies have been implemented to characterize abdominal and pelvic lesions [
10‐
12]. Among them, one of the most promising applications is the detection of PCa with DWI.
Numerous studies have explored the diagnostic performance of DWI in detecting PCa with widely varied sensitivity and specificity (29–94 % and 39–100 %, respectively) [
13‐
33]. Recently, there have been several meta-analysis articles [
34‐
38] regarding this topic with slight differences in the pooled results. Therefore, this study aims to evaluate the diagnostic performance of DWI in detecting PCa, through a synthesis of a larger number of published experimental research, and to deduce its clinical utility.
Discussion
PCa is more likely to be diagnosed in patients with advanced age, especially over the age of 60 [
1]. Accurate cancer detection and evaluation is essential to focal treatment planning [
47]. Diagnosis of PCa with quantitative DWI involves the apparent diffusion coefficient (ADC), which is lower in PCa than normal prostate tissue [
48]. Previous studies have demonstrated that DWI was a feasible method to detect PCa. Meanwhile, DWI was also considered to play an important role in monitoring therapy response, evaluating cancer aggressiveness and metastasis, guiding targeted biopsy and patient follow-up [
49]. Nevertheless, all applications referred to above were based on an accurate diagnosis of PCa.
In this study, we explored the ability of DWI in detecting PCa. Results showed that for prostate cancer detection, DWI had high specificity (90 %) and relatively low sensitivity (62 %). Both sensitivity and specificity showed large variability. Next, we focused on the SROC curve, which gave an AUC of 0.8991 indicating a good, but not excellent, diagnostic performance. This result was in accordance with previous studies [
34,
35,
37,
38]. Moreover, owing to the larger number of original studies and extensive statistical analysis, results of this study make up for some limitations that previous studies acknowledged and gave objective and practical suggestions for.
There was significant heterogeneity between the included studies. To explore the source of heterogeneity, we first eliminated threshold effect through the ROC plane. Meta-regression analysis showed that study population, patient age, study design, reference standard, diagnostic threshold, time interval and type of coil did not contribute to the heterogeneity statistically. Patient condition, magnetic field strength and MRI reviewer blinding to other test results and clinical information were thought to be the most important variable sources of heterogeneity. The results of sensitivity analysis for 19 studies were similar to the original results, indicating that the results of this study were reliable.
Detectability of PCa depends on tumour characteristics including tumour Gleason score, histological volume, architecture and location [
50]. There was greater sensitivity for tumours of higher grade or larger size [
51]. Numerous studies have suggested strong correlation between Gleason score and tumour volume and between PSA level and tumour volume [
52,
53]. The level of serum PSA is related to patient condition, such as tumour volume and progression, and is easily affected by multiple factors [
54]. In this meta-analysis, tumour volume was not described in much detail, and the level of PSA varied widely from 0.48 to 1,000 ng/mL. We performed a subgroup analysis between studies with the mean PSA < 20 ng/mL and ≥20 ng/mL. Table
5 shows that patients with high PSA level had higher sensitivity and relatively low specificity when diagnosed with DWI. Meanwhile, the
Q statistics and
I
2 decreased significantly within the two subgroups, especially the high PSA group. No significant difference was found in the mean Gleason score between the two groups. Further investigation of tumour characteristics was limited because data on a per-patient basis were required. Therefore, we suggest that large-scale, quality-controlled studies specifically addressing those factors should be conducted in the future.
In the subgroup analysis, we compared the effect of two magnetic field strengths, 3.0T and 1.5T. High field strength (3.0T) demonstrated high sensitivity and specificity for the detection of PCa with DWI (Table
5). Prostate imaging at 3.0T benefits from higher signal-to-noise ratio (SNR), and enables either an increased spatial resolution or an increase in SNR of the ADC maps [
55]. For this reason, improvements in the localization and detection of PCa were expected [
26,
56,
57]. However, some studies [
58,
59] reported that DWI performed at 3.0T generally had similar ADC values, but worse image quality compared with 1.5T, suggesting that there was no significant advantage for the diagnosis of PCa by 3-T MRI over 1.5-T MRI. Therefore, to take full advantage of the benefits of high field strength, improved acquisition techniques are required.
There are as yet no standardized DW-MRI techniques, and a large variety of imaging parameters exist for DWI in the number and size of
b values, diagnostic threshold and coils. Performing DWI requires at least two
b factors which allows for the calculation of ADC. High
b value permits high diffusion weighting, and tumour tissue often has higher signal intensity or lower ADC values on ADC maps compared with native tissue [
60]. The typical
b value for prostate imaging varies in the range 0–1,500 s/mm
2. Some studies [
61,
62] suggested that the use of
b = 2,000 s/mm
2 is diagnostically superior to that of
b = 1,000 s/mm
2. However, other studies [
15,
17] reported that for predicting PCa, the optimal
b value for 3.0-T DWI was 1,000 s/mm
2. A recent study also suggested the use of the true diffusion coefficient, which can be obtained using a minimum of three
b values and is less influenced than the ADC by
b value selection [
63]. In this meta-analysis, there was profound discrepancy in the choice of
b values between individual studies, ranging from 0 to 2,000 s/mm
2. We failed to analyse the potential influence of different
b values because three or more
b values (median, 3 values/study; range, 2–6) were used to acquire different diffusion weighting in the same study. Moreover, the considerable overlap of ADC between cancer and noncancerous tissue made it difficult to determine a diagnostic threshold [
64,
65]. Besides, the level of suspicion (LOS) was estimated in six studies [
15,
25,
27,
29,
31,
33] for qualitative interpretation of DWI results, which made a uniformed image interpretation even harder. In brief, all those challenges prompted further optimization of image acquisition and interpretation.
An endorectal coil provides a superior SNR compared with a pelvic phased array coil but causes the displacement of the prostate gland, reduced patient compliance and increased susceptibility artefacts [
66,
67]. The subgroup analysis results showed that for the detection of PCa, sensitivity of DWI with an endorectal coil used was significantly higher (0.77 [95 % CI 0.73–0.80]) than without an endorectal coil (0.60 [95 % CI 0.58–0.61]). Therefore, although the overall diagnostic accuracy was not improved, the use of an endorectal coil was recommended for increased sensitivity.
The subgroup analysis also found that studies which took radical prostatectomy as reference standard had a slight improvement in specificity, while sensitivity dropped dramatically from 73 % to 59 % compared with studies that took prostate biopsy as reference standard. We speculated that this might be caused by the high false-negative rate of prostate biopsy [
2]. Over the last few years, lots of effort has been made on the optimization of initial prostate biopsy in clinical practice, and inherent within those optimizations is variation of the core number, location, labelling and processing for pathological evaluation [
68‐
72]. To date, there is no consensus in this regard. New imaging methods that allow targeted biopsy (such as MRI-guided biopsy) were reported to be possible and improve the assessment of true tumour aggressiveness [
73]. Hopefully, with the development of new imaging methods, we expect the role of prostate biopsy in the diagnosis of PCa to be near to perfect.
Furthermore, given the fact that about 70–75 % cancer arise in the peripheral zone (PZ), we guessed that a separate imaging protocol specific to PZ tumours might lead to more accurate diagnosis, because tumours arising in the PZ tend to be more aggressive [
74,
75]. Thus, we analysed the diagnostic performance of DWI in detecting peripheral zone PCa alone within eight studies [
13,
16,
20,
21,
24‐
26,
28]. The pooled sensitivity and specificity were 0.79 (95 % CI 0.75–0.83) and 0.85 (95 % CI 0.82–0.86), respectively. Sensitivity was significantly high in detecting peripheral zone PCa compared with all regions evaluated together (sensitivity 62 %). However, the overall diagnostic accuracy was not improved as expected compared with the original results (AUC 0.8991). It was worth noting that there was still significant heterogeneity between these eight studies. Therefore, this conclusion remains to be confirmed by further investigation and should be considered with caution.
There are still many challenges in the diagnosis of PCa. The current pathway for men suspected of having PCa results in overdiagnosis and overtreatment, as well as systematically missed significant tumours in the anterior and apical parts of prostate gland [
76]. Additionally, tumours located in the transition zone are more challenging to detect [
77]. Although many MR imaging methods (T2WI, DWI, DCE-MRI and MRS) have been explored in the detection of PCa, they all have substantial limitations [
78]. Therefore, the combined use of DWI with T2WI, DCE-MRI or MRS was recommended [
79].
We should acknowledge some limitations of this meta-analysis. First, although a comprehensive literature search was performed in several authoritative databases, neglecting a grey literature search and non-English-language articles might have introduced potential publication bias. Second, the image interpretation of DWI was performed for the most part qualitatively, and in many studies blinding was either unclear or absent. In the subgroup analysis, studies designed without (or unclear) MRI reviewer blinding to other information yielded higher results for both sensitivity and specificity compared with studies which were designed blinded. Therefore, an objective interpretation of image results was queried. Third, although QUADAS was adopted to ensure high quality of included articles, there were still many retrospective studies, and many participants in the included studies were diagnosed or suspected of prostate cancer on the basis of ultrasound, CT or other clinical information, and therefore might have caused patient selection bias (Fig.
1) and a greater sensitivity, which was confirmed by the subgroup analysis results.
In conclusion, our meta-analysis showed that DWI was an informative MRI modality and had moderately high diagnostic accuracy for the detection of PCa. Further application of DWI in detecting PCa requires the optimization of image acquisition techniques and interpretation.