The combined value of mpUS and mpMRI-TRUS fusion for the diagnosis of clinically significant prostate cancer

The cancer-associated death of prostate cancer (PCa) was ranked the fifth highest among men in 2020 worldwide. In more than half the countries globally, PCa is the most common type of cancer [1]. Several methods are used for detecting PCa, such as determining prostate-specific antigen (PSA) levels, digital rectal examination (DRE), magnetic resonance imaging (MRI), and ultrasound. However, PSA or DRE has a high false positive rate that leads to a large number of unnecessary systematic biopsies (SBs) [2]. MRI offers better anatomical resolution and high accuracy in PCa diagnosis compared with other methods, but MRI guide TB (in-bore TB) is rather time-consuming [3]. In recent years, mpMRI-TRUS fusion imaging has garnered attention, enabling sonographers to perform TB under real-time MRI guidance. Fusion imaging combines the sensitivity and specificity of MRI with the real-time and practicality of TRUS, which can detect PCa more accurately and guide TB. It has been used extensively in several hospitals around the world [4].

Compared with PCa, csPCa is more closely related to mortality, and hence increasing csPCa detection rates is the key to reducing mortality. At the same time, reducing clinically insignificant PCa (ciPCa) detection rates is important for improving patients’ quality of life. Hence, accurately identifying csPCa and providing more effective disease-related information to the clinics is crucial.

New ultrasound technologies such as CEUS and TRES have a higher PCa detection rate than conventional TRUS. These new techniques are immensely helpful in diagnosing and treating PCa [5]. Previous studies have reported that CEUS and TRES could detect PCa more accurately by monitoring vascularization in the prostate tissues as well as the hardness of the tumor [6]. Moreover, they are easily accessible to a urologist for conducting routine PCa examinations. However, only a few studies have reported the accuracy of mpMRI-TRUS fusion imaging. Therefore, for increasing the diagnostic accuracy of csPCa, we aimed to evaluate the combined value of mpUS and mpMRI-TRUS fusion for diagnosing csPCa.

According to the 2020 guidelines of the European Association of Urology, mpMRI should be used as a routine application before prostate biopsy [16]. Meanwhile, mpMRI-TRUS fusion imaging has been advocated for clinical application. Xie [17] analyzed the literature on mpMRI-TRUS fusion imaging from 2012 to 2021 and showed that the fusion imaging-guided TB had a higher detection rate of csPCa. Similarly, we confirmed that TB was higher than SB for detecting csPCa (p < 0.05) but our results included the TB guided by mpUS. TB detected 12 PCa missed by SB, 10 of which were csPCa. If only TB was used, 12 (9.9%) PCa would be missed, including 9 ciPCa and only 3 csPCa (2.5%). TB upgraded two patients diagnosed with ciPCa in SB to csPCa. Therefore, TB could detect csPCa more effectively than SB.

Over-diagnosis of PCa is a common problem in the medical profession. One of the reasons is that SB based on abnormal PSA and DRE has the disadvantage of over-detecting ciPCa, missing the diagnosis of csPCa, and underestimating the invasion of cancer foci [18]. To avoid over-diagnosis and treatment of PCa, increase the long-term quality of life of patients, and improve the accuracy of biopsy, it is imperative to diagnose csPCa accurately. We found that TB improves the detection rate of csPCa, which is valuable for clinical diagnosis and risk assessment of csPCa so that patients who benefit from treatment more than observation and follow-up can be effectively selected. Thus, TB has a considerable guiding significance for clinical treatment.

The Cochrane database of systematic reviews suggests that the MRI pathway is superior to SB in making a precise diagnosis of csPCa, albeit it still misses some csPCa. Therefore, it is imperative to conduct further research to resolve this concern [19]. To improve the detection of prostate cancer lesions, we performed CEUS and TRES imaging feature analysis based on the target region of mpMRI-TRUS fusion imaging. Our results suggested that the mpUS characteristics between the PCa and non-PCa groups were statistically significant (p < 0.001), which is similar to the observations reported by Shinohara, Sano, et al. [20, 21]. With regard to two-dimensional ultrasonography, the literature has well documented that 80% of PCa emerges in the peripheral zone of the prostate and frequently has irregular edges compared with benign prostatic hyperplasia (BPH) due to aggressive growth [22]. The inward spread of PCa was opposed by the surgical capsule between the central gland and the peripheral zone. As a result, they tended to spread outward. The capsular protrusion, thickening, irregular interruptions, and contour asymmetry were associated with capsular invasion. When PCa continues to grow, it breaks through the surgical capsule and grows inward and upward [23], which may be why the aspect ratio was ≥ 1. BPH showed different echoes according to the different components of glands and stroma, most of which are isoechoic with regular edges. Big nodules in the peripheral zone tend to show the characteristics of a capsular bulge, but, in the central glands, they depended on the location, which usually contains normal tissues between them and the capsule. Microvascularization and arteriovenous shunts are a part of tumor-specific pathophysiological processes characterized by high microvessel density that is highly tortuous, disordered, and irregular with shunts. Therefore, PCa is characterized by early contrast agent enhancement and chaotic vascular structure caused by excessive arterial formation, which is manifested as a fast forward enhancement, fast backward enhancement, hyperperfusion, and diffuse enhancement on CEUS. The reduced cross-sectional area of the functional blood vessels in the tumor tissues increased the tortuosity and flow resistance and diminished the perfusion, which also manifested as hypoperfusion/nonperfusion [24]. When compared with PCa, BPH mainly occurs in the central gland, and its enhancement pattern was similar to that of the prostate tissues, which enhanced and disappeared synchronously with the prostate tissue. Some researchers have studied surgical specimens and found fresh blood vessel regeneration in BPH nodules. The blood supply of the external glands is relatively reduced because of the compression of the enlarged internal glands. Therefore, BPH can also manifest as fast forward and backward enhancement as well as hyperperfusion. In the benign tissues, capillaries are mostly confined to the peri-glandular stroma close to epithelial cells, rather than being irregularly distributed as in tumor foci. Increased extracellular matrix deposition and greater adherence to the surrounding tissues contribute to an increase in the hardness of the cancerous tissues when compared to that in the normal tissues; as a result, it manifests as an area with less strain or even no strain on TRES [14]. BPH tissue is less stiff, hence the strain is also relatively homogeneous and symmetrical.

In this study, we performed TB of 31 lesions that were reported negative by MRI but positive by mpUS imaging features, with pathological findings of 13 csPCa and 18 non-PCa. The additional use of mpUS in the targeted region increased the detection of csPCa by 12.4% (13/105). The additional use of mpUS examinations in the targeted area improved the detection of csPCa and provided more efficient diagnostic information for fusion imaging.

To the best of our knowledge, there are only a few studies on the combined application of MpMRI-TRUS fusion imaging and mpUS. Maxeiner et al. investigate whether mpUS can further characterize mpMRI-suspected lesions through fusion and found that mpUS are strong predictors of PCa detection and PI-RADS 5 prediction; therefore, mpUS can be used as an additional tool as well as to reassure the PI-RADS score [25]. However, instead of assessing a combination, the researchers assessed the value of each method individually for diagnosing PCa. Brock et al. found that the fusion of mpMRI with TRES could improve the visualization of PCa lesions when compared to that by MRI alone [26]. Pepe evaluated 21 patients with negative DRE and a past negative biopsy, but with elevated PSA values and concluded that mpUS did not improve the accuracy of TB in diagnosing csPCa, which is inconsistent with our results [27]. First, the inclusion criteria are different from ours, which results in the lack of evaluation of some cases, especially those on the biopsy of naive patients. Second, they did not perform TB in the CEUS or TRES positive areas, therefore it is unknown whether mpUS would have been diagnosed csPCa that were missed by TB. Third, the false negative rate of mpMRI for csPCa (4/21 cases) has not been correlated to the mpUS findings. Finally, the sample sizes are too small, requiring the evaluation of a greater number of cases to reach a concrete conclusion.

A single imaging method demonstrates limited value in diagnosing cancers. It needs to be combined to maximize the diagnosis of csPCa, which can give patients the most accurate disease information and further guide the clinical treatment. mpUS can be expected to detect plausible characteristics of PCa and provide additional information for patients that can be helpful for their treatment. In the future, further research is required to determine the role of fusion imaging in these patients and imaging at the molecular imaging level to determine which patients may benefit the most from this diagnostic procedure.

The disadvantages of this study are as follows: First, only 20 patients underwent radical prostatectomy and for the remaining 140 patients, we used puncture results as the gold standard. All patients involved underwent biopsies for the first time. Therefore, if the patient’s biopsy result was negative, radical prostatectomy was not performed, leading to the missed diagnosis of low-grade and some advanced PCa to some extent. However, radical prostatectomy is not always prescribed for every patient owing to more complications and elaborate surgical criteria. Second, the high dependence of the PI-RADS distribution on the prevalence of csPCa is the reason for the lack of consensus on PI-RADS category 3 or 4 as positive. In European biopsy-naïve patients, the percentage of PI-RADS 3 potentially indicates the “certainty” of diagnosis and thus that of image quality and reading. However, according to our results, compared with PI-RADS category 3, PI-RADS category 4 produced a better result. Another study reported that the best cutoff for differentiating benign lesions from PCa was PI-RADS category 3. The best cutoff for differentiating low-risk PCa from csPCa was PI-RADS category 4. Therefore, for csPCa evaluation, we used PI-RADS category 4 or more as positive [28].

However, unlike some previous studies, we performed pre-biopsy MRI for patients without contraindications to avoid selection bias instead of biopsy based on MRI risk assessment. Moreover, we not only examined mpMRI-TRUS fusion imaging but also combined it with mpUS. As a result, the imaging features of the fusion region were further characterized, which was deemed valuable for the accurate localization of PCa and the subsequent puncture process. By combining different techniques, the clinical detection limitations of each imaging modality can be balanced. In the future, we believe that this imaging modality can become a valuable tool for the clinical diagnosis of prostate cancer and further guide clinical decision-making.

We found that TB can be used to improve the detection rate of csPCa, and thus, effectively used in the diagnosis and risk assessment of csPCa. The mpUS characteristics of the target areas can provide valuable diagnostic information for mpMRI-TRUS fusion imaging, which can be helpful for the further visualization of PCa foci. Eventually, we believe that the combination of mpUS with mpMRI-TRUS fusion imaging possesses a higher diagnostic value for csPCa and can provide valuable guidance for subsequent clinical treatment.