Novel trends in transrectal ultrasound imaging of prostate gland carcinoma.

Carcinoma of the prostate gland is the most common neoplasm in men. Its treatment depends on multiple factors among which local staging plays a significant role. The basic method is transrectal ultrasound imaging. This examination enables imaging of the prostate gland and its abnormalities, but it also allows ultrasound-guided biopsies to be conducted. A conventional gray-scale ultrasound examination enables assessment of the size, echostructure and outlines of the anatomic capsule, but in many cases, neoplastic lesions cannot be observed. For this reason, new sonographic techniques are implemented in order to facilitate detectability of cancer. The usage of contrast agents during transrectal ultrasound examination must be emphasized since, in combination with color Doppler, it facilitates detection of cancerous lesions by visualizing flow which is not observable without contrast enhancement. Elastography, in turn, is a different solution. It uses the differences in tissue elasticity between a neoplastic region and normal prostatic parenchyma that surrounds it. This technique facilitates detection of lesions irrespective of their echogenicity and thereby supplements conventional transrectal examinations. However, the size of the prostate gland and its relatively far location from the transducer may constitute limitations to the effectiveness of elastography. Moreover, the manner of conducting such an examination depends on the examiner and his or her subjective assessment. Another method, which falls within the novel, popular trend of combining imaging methods, is fusion of magnetic resonance imaging and transrectal sonography. The application of multidimensional magnetic resonance imaging, which is currently believed to be the best method for prostate cancer staging, in combination with the availability of a TRUS examination and the possibility of monitoring biopsies in real-time sonography is a promising alternative, but it is associated with higher costs and longer duration of the examination. This paper presents the most important novel trends in transrectal imaging in prostate cancer diagnosis based on the review of the articles available in the PubMed base and published after 2010.

Introduction

Carcinoma of the prostate gland is the most common neoplasm in men(. One of the breakthrough moments in early diagnosis and treatment of this disease was the introduction of prostate specific antigen (PSA) measurement in the serum(. This resulted in increased detectability of the disease in patients with cancer limited to the prostate gland without metastases who can be treated radically, by means of both radical prostatectomy and radiotherapy.

In these patients, accurate local cancer staging plays a important role. It is one of the parameters determining the choice of adequate treatment and of certain elements of a surgical procedure, such as performance of extended lymphadenectomy or removal of the neurovascular bundle, for instance because of a visible lesion that adheres to the prostatic capsule at the length of over 20 mm, which increases the risk of locally advanced carcinoma(. Another important element in preoperative assessment of patients with localized prostate carcinoma is the size of the prostate gland which may, to some extent, limit the effectiveness of radiation techniques, including brachytherapy. Detection of lesions in TRUS (transrectal ultrasound examination) in a patient diagnosed due to elevated serum PSA but normal digital rectal examination results in restaging of the disease from T1c to T2 (including T2a/T2c depending on the presence of foci in both lobes or in only one of them).

Therefore, it may be concluded that a TRUS examination provides a lot of valuable information that considerably affect treatment of patients with localized prostate cancer. However, such an examination is not flawless. The limitations include subjectivity of assessment (which largely depends on the physician's experience), poor repeatability of the examination and, frequently, its ambiguity. Hence, in accordance with the guidelines of the European Association of Urology (EAU) and American Association of Urology (AUA), a multiparametric nuclear magnetic resonance examination (NMR) with the use of an endorectal coil is currently considered a reference method in local staging of prostate cancer(.

A TRUS examination still remains a valuable technique with proven diagnostic value. A range of novel techniques and rich literature indicate continuous and dynamic development of this imaging technique. Apart from the introduction of high-frequency transducers, tissue harmonic imaging, histoscanning and color flow mapping (figs. 1–5), the following developments of transrectal ultrasound examination of prostate cancer can be distinguished:

Fig. 1

TRUS with a 9 MHz transducer

Fig. 5

Prostate gland in color flow mapping (CFM)

contrast-enhanced imaging:

gray-scale;

color Doppler;

power Doppler;

elastography;

MRI and TRUS image fusion.

TRUS with a 12 MHz transducer

Prostate histoscanning

Prostate harmonic imaging

Contrast-enhanced ultrasound imaging

The influence of gas bubbles on striking echo enhancement was observed for the first time at the University of Rochester. Three different contrasting agents were used: indocyanine green, physiological saline and dextrose in water. Energetic injection of these substances through a thin needle resulted in formation of tiny bubbles with the diameter of several microns. The improvement in M-mode echocardiography of the aorta root and mitral insufficiency were striking(.

The subsequent pioneering investigations on the enhancement mechanism (differences in acoustic impedance between blood and the agent administered, turbulences resulting from injection and presence of bubbles) were carried out by Kremkau(. In the first attempts of using spontaneously formed bubbles, their rapid disappearance in the vascular bad was observed. The smallest bubbles were the first to disappear – in less than 1 second, due to surface tension. Big bubbles, in turn, were blocked by the pulmonary capillary bed.

The dynamics of encapsulated contrast agents (thin coating, lipid membranes) was studied in many laboratories(.

Nowadays, suspensions of small gas bubbles with the diameter of several micrometers are called ultrasound contrast agents. Because of very low density of gas, its acoustic impedance is several thousand times lower than impedance of blood, thanks to which reflection/scattering of the ultrasound wave on gas bubbles is several thousand times greater than on blood cells. Gas bubbles exhibit resonant properties. The simplified formula for the resonant frequency of the bubble is:

where: f denotes bubble resonant frequency (in MHz), d – bubble diameter (µm)

In currently used contrast agents, the diameter of gas bubbles ranges from 1 to 3 mm which results in resonance frequency from 2 to over 4 MHz.

The first stable microbubble suspension which became commercially available was obtained in 1990 (. Nowadays, ultrasound contrast agents are suspensions of tiny gas bubbles in various solutions: albumin, galactose or lipid. Depending on the medium in which the gas is placed, the suspensions have different compressibility which is an important parameter that determines the physical features of contrast behavior under the ultrasonic wave. Other significant parameters are: the time in which microbubbles persist in the circulation and the amount of energy emitted by the US system that is needed to destroy the structure of the contrast agent(. Due to the fact that the first-generation contrast agents were characterized by poor ability to pass to the prostatic microcirculation, they were not useful in diagnosing prostate cancer. Following the introduction of the second-generation contrast agents, which are characterized by a small diameter of gas bubbles – from 1 to 10 µm (e.g. Sonadozid), it became possible to reach tiny vessels, also the prostatic ones, not visible in a conventional Doppler TRUS examination due to a weak signal. An example of such a substance may be octafluoropropane in a lipid solution (perflutren) in which the diameter of gas bubbles is lower than 1 µm.

The most popular ultrasound contrast agent is SonoVue (Bracco, Italy), a blood pool agent. It does not extravasate into the interstitial space. The average diameter of microbubbles is 2.5 microns. They easily pass through the pulmonary vascular bed and enter the arterial circulation. SonoVue microbubbles consist of sulfur hexafluoride (SF6) stabilized by a thin membrane with external hydrophilic surface and internal hydrophobic surface.

Contrast-enhanced TRUS may be applied to various US methods: gray-scale as well as color and power Doppler imaging. As for the gray-scale imaging, harmonic imaging is particularly interesting, especially recording movement of the brightest pixels (this technique, called maximum intensity projection, enables the assessment of microcirculation) and a technique that uses the flash replenishment effect in which by probing the tissue with enhanced power impulses (Mechanical Index – MI amounts to 1.9), bubbles with contrast are destroyed and subsequently, imaging with low power (MI below 0.3) visualizes how the vascular bed refills with contrast. This technique is superior in visualizing the morphology of the prostatic vascular system as well as the size and intensity of flow within pathological lesions(.

In one of the first works by Halpren(, sextant biopsy conducted in 40 patients based on a conventional gray-scale image and color Doppler was compared with targeted biopsy based on a contrast-enhanced image. The initial results demonstrated that the probability of targeting a cancer focus was 3.5 times greater following the administration of a contrast agent. Further observations in a larger group of 301 patients confirmed these results: 11% of the cases of cancer were detected only on the basis of US-guided biopsy following contrast agent administration, but in 20% of cases, cancer was detected with the use of sextant biopsy, which suggests that systemic biopsy is still an indispensable element of collecting prostate biopsy.

Further development of contrast enhancement and the flash replenishment technique gave similar outcomes. It was demonstrated that the probability of detecting cancer in targeted biopsies was higher than in systemic ones (13% vs 8%). Limiting the examination to collecting samples from the lesions would lead to the failure to detect 28% of lesions. Additionally, no difference was observed in the Gleason grade between cancers detected by the two types of biopsy.

The more advanced techniques also include the method of determining specific contrast response to the impulse within nonlinear echo properties on the first and second harmonic (cadence contrast pulse sequencing), which improves the technique of monitoring prostate biopsies in contrast-enhanced TRUS examinations(. The authors analyzed the results of biopsies conducted in 44 patients according to the following protocol: 10 cores according to the adopted scheme and 5 additional cores based on lesions detected after the administration of the contrast agent. Targeted biopsy detected cancer in 80% of patients (35 of 44) whereas random biopsy detected the disease in 34% of patients (15 of 44). The application of harmonic imaging additionally enhanced by a contrast agent improved the sensitivity and specificity thanks to obtaining images of perfusion – contrast bubbles passing through the tissue. The resolution in this technique is comparable to that achieved in a Doppler examination.

A characteristic feature of a neoplastic process is the formation of own blood vessels in the process of neoangiogenesis, which is also observed in prostate carcinoma. The study of Brawer et al.( revealed that the detection of abnormal foci of enhanced vascularity in the prostatic parenchyma correlated with the diagnosis of carcinoma. Some authors also observed a correlation with greater local advancement (cT3)(. In order to obtain a reliable image of prostatic vascularity, it is necessary to perform a TRUS examination in the lithotomy position. Halpern et al.( demonstrated that a standard left lateral position disturbs flow (probably due to a unilateral compression on the intraprostatic vessels)(.

A typical method for assessing vascularity of the prostate gland and focal lesions is Doppler examination, either color of power Doppler. No significant difference between these methods was observed in the context of prostate cancer detection(. Despite promising initial results, these methods have not been introduced to the standards of prostate assessment in TRUS.

Increased vascular flow is also observed in the course of inflammation and benign hyperplasia of the prostate gland. A flow pattern characteristic of cancer, which would allow differentiation between areas of enhanced flow, has not been determined. Therefore, a B-mode image of lesions is compared with the image of vascularity following the administration of a contrast agent. Since the majority of patients diagnosed due to a suspicion of prostate carcinoma also manifest benign hyperplasia of the gland causing enhanced flow, this is a frequent diagnostic challenge.

In 2011, Xie et al.( conducted conventional TRUS examinations and biopsies guided by a power Doppler image as well as examinations using an imaging technique with low MI, which extends contrast's “life” (contrast tuned imaging, CnTI), following the administration of the contrast agent SonoVue with the use of power Doppler. They enrolled 150 patients diagnosed due to a suspicion of cancer based on elevated serum PSA level. Flow in the peripheral zone of the prostate was assessed according to the following scale: rapid contrast uptake, enhanced contrast uptake, flow asymmetry, poor contrast uptake or the lack of uptake. The comparison of the results obtained in systemic biopsies with those obtained in targeted biopsies with contrast-enhancement showed no statistically significant differences in the number of patients in whom carcinoma was diagnosed.

For many years, 5-alpha-reductase inhibitors (e.g. dutasteride) have been used to treat the lower urinary tract symptoms caused by benign prostatic hyperplasia (BPH). One of the effects of this medicine is decreasing blood flow in the prostate gland as a result of reducing the number of vessels, particularly those in the region of benign hyperplasia. Such an effect is observed after 7 days and its maximum is achieved after 14 days. A delayed consequence of such an effect is decreased volume of the prostate.

The first reports (Ives et al.)( were confirmed in a paper published by Mitterberger in 2007(. The authors conducted studies in the group of 36 asymptomatic volunteers with PSA > 1.25 ng/ml (mean 4.61 ng/m in the range from 1.25 to 8.0 ng/ml). They underwent a TRUS examination with flow assessment in power Doppler mode following contrast administration and further examinations in the 7th and 14th days of treatment with dutasteride. The TRUS examination showed decreasing flow in the certain lesions.

On the 14th day of treatment, at least one focus with preserved enhanced flow following contrast enhancement was localized in each patient. Biopsies were conducted for each lesion. However, in total, the number of samples collected was not greater than five. Moreover, a standard systemic biopsy was conducted which involved the collection of 10 samples. Cancer was detected in 12 patients: in each case positive results were obtained based on biopsies targeted to lesions with enhanced vascular flow. In the case of systemic biopsies, cancer was detected in 6 patients. These results are promising, but need confirmation in studies among a larger group of patients(.

Imaging with three-dimensional generation of the prostate image may also be potentially relevant in prostatic cancer diagnosis. Thanks to thorough assessment of the gland in different planes, particularly of the prostatic capsule, seminal vesicles and the trapezoid area, a more accurate staging of localized prostate cancer is feasible. In 2007, the paper by Mitterberger(, which analyzed biopsy results of 180 patients who subsequently underwent radical prostatectomy, revealed that a 3D TRUS examination detected cancer that infiltrate the prostatic capsule with the sensitivity level of 84% and specificity of 96%. It also showed that in 14 of 16 cases (87.5%), invasion of the seminal vesicles was accurately identified(.

A 3D reconstruction is also used in fusing NMR and TRUS images. This technique will be discussed in greater detail below. A characteristic feature that distinguishes this method from other techniques presented herein is the ability to accurately determine the size of the prostate gland and individual zones e.g. the central zone (prostatic adenoma). Thanks to the continuous improvement of the US system software, performing such calculations became faster and easier, which influenced the popularity of this method among its users. The publications concerning this issue showed that determining the volume of the prostate based on a 3D reconstruction is currently the most accurate method of measuring its volume(. This parameter plays an important role in qualifying patients for brachytherapy and for treatment of benign prostatic hyperplasia. Depending on the size of prostatic adenoma, various methods of removing the bladder outlet obstruction caused by BPH may be recommended: ranging from a simple incision of the prostate to transurethral electro-resection or other methods of thransuretheral removal of adenoma, to laparoscopic or open adenomectomy.

Elastography

One of the basic examinations in the diagnostic process of prostate carcinoma is a digital rectal examination (DRE). Suspicious findings and at the same time, indications for biopsy, are: asymmetry of the prostate and change in the firmness or detection of uneven surface of the prostate in the form of a palpable nodule. Elastography in a way reflects DRE examination in transrectal sonography. Neoplastic tissue in the prostate gland is characterized by decreased elasticity which results from increased cellular density(. This phenomenon is the basis of using elastography for detecting cancerous foci in the region of the prostate gland.

The first application of such imaging was presented in 1991 by Ophir et al.( The change of the prostatic cellular density is coded in the form of a color map, in which blue usually denotes tissues with the lowest strain, green denotes tissues with moderate strain and red – tissues with the greatest strain. Thus, a colored image of the prostate is obtained which reflects elasticity characteristics of individual areas – in accordance with the guidelines concerning detection of neoplastic foci(. The improvements introduced by Pesavento enabled examinations in real-time(. The outcomes of the study conducted by Brock et al.( are a good example of the possibilities offered by this method. Two hundred and twenty nine patients with carcinoma of the prostate gland qualified to radical prostatectomy underwent a gray-scale TRUS examination with elastography. The authors divided the prostate into six regions and decided to analyze the possibility of visualizing infiltration of the capsule and ability to detect neoplastic foci. The results obtained indicate a statistically significant superiority of elastography in detecting foci of carcinoma compared to a conventional TRUS examination (66.4% vs 24%). More importantly, similar results were obtained for infiltration of the capsule. In this case, the sensitivity and specificity of elastography amounted to 38% and 96% respectively whereas the respective values in conventional TRUS were 15% and 97%.

Although numerous papers indicate that elastography is superior to conventional TRUS in terms of cancer detectability, it has not become a commonly used method(. A high percentage of accurate elastography-guided biopsies may lead to a decrease in the number of biopsy cores, which influences the tolerability of the procedure(. The technique of this examination is largely dependent on the physician's experience. According to Pallwein et al.(, it takes approximately 3–6 months to learn how to conduct this examination in order to obtain reproducible outcomes(. In order to improve repeatability of results, examiner modify the strength of pressure applied with the transducer in TRUS and observe the color scale at the side of the monitor which shows the strength of tissue compression.

The paper of Pallwein et al. presents a comparison of a conventional 10-core prostate biopsy with biopsy of suspicious lesions detected in elastography(. The authors examined 429 patients in whom prostate biopsy was indicated due to elevated serum PSA level. Carcinoma was detected in 25.4% of patients in systemic biopsies. Neoplastic cells were detected in 48.4% of suspicious lesions in elastography. A thorough analysis of histo-pathological results from each site selected on the basis of elastography revealed false positive results. It showed that the most common cause (51.6%) was inflammation or atrophic process, particularly frequently observed within the base of the prostate gland. The division of the prostate into three regions (the base, the central region and the apex) showed that imaging of the lesions was the most effective within the apex and effectiveness decreased towards the base of the prostate.

Non-cancerous lesions, which may develop in the prostate irrespective of carcinoma, may also affect the result of the examination. Calcifications in the course of inflammation or benign hyperplasia of the prostate are good examples. They are usually localized on the border between the peripheral and transition zones. In such a case, the ability of elastography to differentiate between the character of the tissue within adenoma is considerably limited. Therefore, some of the studies do not involve the analysis of the image in terms of detecting foci with lower elasticity within the transition zone of the prostate gland(.

The extensive meta-analysis conducted by Aboumarzouk et al.( presents very interesting conclusions and observations. The authors reviewed literature concerning the application of elastography in diagnosing carcinoma of the prostate. The majority of papers confirm the fact that the highest detectability of lesions is within the apex of the prostate followed by the central area, and the lowest detectability is within the base. This probably results from the increase in the height of the prostate and consequently, from the increase in the distance of lesions from the US transducer(. Similarly, in the majority of cases, it is possible to detect lesions localized within the peripheral zone, directly adjacent to the rectum. Since in most of the cases (75%), carcinoma is primarily localized in this site, this limitation of the method is not particularly relevant. It should be remembered, however, that infiltration of the transition zone, which indicates local advancement of the neoplastic process, may be unnoticed. On the other hand, numerous authors indicate that the detectability of foci with high Gleason score is greater, which might enable better preoperative staging and correct selection of an adequate form of radical treatment(.

Image fusion

The recommendations of the EAU (the chapter on local staging, i.e. T category, of prostate carcinoma) mention the improvement of resolution in modern NMR scanners. This enables more accurate local staging of prostate carcinoma, e.g. infiltrating the seminal vesicles and prostatic capsule with simultaneous imaging of the lymph nodes in this region(. These data, combined with information obtained during prostate biopsy, may influence the manner of conducting radical prostatectomy in terms of preserving the neurovascular bundles(.

It must be mentioned that NMR is a multiparametric examination that enables assessment of the prostate gland, including focal lesions, in a conventional “anatomic” imaging before and after administration of a contrast agent and together with using additional options – spectroscopy and diffusion weighted imaging (DWI) conducted with the use of a surface coil(. The addition of the option that presents the metabolism in the prostate (spectroscopy) makes it possible to detect highly malignant lesions(, but this method is still not considered a necessary tool in local T staging prior to radical treatment.

The NMR examination, apart from the limitations typical of each imaging method (subjective assessment, dependence on the radiologist's experience), has also certain characteristics that still prevent it from being commonly used in prostate carcinoma diagnosis. Good solutions must be found not only to problems of limited availability of this method, its cost or poor experience of physicians interpreting the results, but also to problems associated with optimizing tools for prostate biopsy during MRI. At present, the system to introduce the needle in the NMR equipment is highly expensive and performing biopsy requires full sedation of the patient and takes more time(. On the other hand, standard prostate biopsy monitored in a TRUS image is an easy procedure which allows US-guided biopsies to be performed in real time. Provided that the examination is performed by an experienced physician, it enables taken biopsy cores from any part of the prostate, such as the apex or seminal vesicles.

The combination of these two imaging methods, i.e. MRI and TRUS, appears to be an interesting and promising method to diagnose prostate carcinoma(. Image fusion consists in performing an NMR examination and transferring the MR images to the US system by means of a CD or USB flash drive. Another step involves specifying reference control points (e.g. the apex of the prostate) or position of the transducer by means of the transducer spatial location detection that uses a magnetic field generator and magnetic field sensors fitted in the transducer case. Experiments conducted on prostate models revealed that it is possible to visualize lesions with the diameter below 3 mm and introduce a biopsy needle when NMR/TRUS image is used for guidance(. This creates potentially very favorable conditions for diagnosing prostate carcinoma, in particular the localized one(.

An example of the paper that analyses results of biopsy conducted on the basis of NMR/TRUS image fusion is the publication of Pinto et al. from 2011(. The authors performed prostate biopsy in 101 patients and compared standard random biopsy (up to 12 cores) with biopsy targeted to lesions visible in NMR (two biopsies per one lesion). A positive result of the targeted biopsy was obtained in 51% of patients. This is a satisfactory result, particularly because the mean PSA level in this group was 5.8 ng/ml and a DRE examination was negative in 90% of patients. The lesions were divided according to cancer suspicion level as: low, moderate and high suspicion. The following values of positive results were obtained in the groups: 27.9%, 66.7% and 89.5%(.

Moreover, Miyagawa et al.( presented the results of MRI/TRUS fusion prostate biopsies conducted in 85 patients in 2010. In the case of 52 patients, this was the second biopsy after a negative result had been obtained in standard TRUS-guided biopsy. The authors obtained 61% of positive results. This is a considerably better result than the one obtained in a conventional TRUS examination, in which a repeated biopsy usually results in 10–20% of positive outcomes. In the analyzed group, 17 patients were diagnosed with carcinoma on the basis of MR-guided biopsy only; targeted and random biopsies were positive in 27 patients and random biopsy was positive merely in 7 patients (in this group, image fusion was not performed in 3 patients due to technical reasons). Carcinoma was not diagnosed in only 4 patients compared to 17 negative results obtained in random biopsy(.

The NMR/TRUS image fusion may also be used in treatment of prostate carcinoma by means of brachytherapy – in planning spatial placement of radioactive agents. A paper concerning this issue was presented by Reyner et al.(

In the light of the promising reports regarding NMR/TRUS image fusion, attention should be paid to the paper of Fiard et al.( form 2013 that addresses the issue of subjective NMR image assessment. According to the recommendations of the European Society of Uroginecologic Radiology, the Prostate Imaging-Reporting and Data System (PI-RADS) scale was used to standardize descriptions and thus, eliminate discrepancies between descriptions of imaging examinations(. In order to accurately superimpose images, 3D TRUS examinations were performed in the lithotomy position. The suspicious images previously marked in NMR were automatically superimposed on a TRUS image. This stage lasted approximately 23 minutes.

The examination was performed in patients with carcinoma suspected on the basis of a DRE examination and elevated serum PSA level (PSA > 4 ng/ml). Following MRI, the patients was referred to TRUS and prostate biopsy. As in other studies, random 12-core prostate biopsy was conducted in accordance with current EAU guidelines. The random systemic biopsy was supplemented with samples collected from suspicious areas marked during the NMR examination. Carcinoma was confirmed in TRUS-guided biopsy in all patients with a positive NMR result and, additionally, cancer cells were also detected in 3 patients with a negative MRI result. More importantly, the DRE examination also failed to detect any abnormalities in these 3 patients. Based on the degree of malignancy expressed as Gleason score, which in the three patients mentioned above was < 6, it was decided to implement active surveillance since these instances of cancer were considered clinically irrelevant.

The asset of this study was monitoring the biopsies in a 3D TRUS image. Superimposing the 3D image on the MRI image with marked focal lesions allowed the marked lesion to be targeted with a needle in 86% of cases. In each lesion marked for biopsy in such a way, one core was sufficient to collect representative material for a histopathological examination. This technique is superior to 2D TRUS since, apart from good visualization of focal lesions, it enables superior visualization of lesions in the anterior aspect of the prostate (i.e. in the transition zone) which is not sufficiently visible in a conventional 2D TRUS examination. In one patient, a suspicious focus was observed in the MRI image and the biopsy confirmed the presence of prostate carcinoma. Moreover, MRI/3D TRUS fusion enabled detection of carcinoma of a higher malignancy degree according to the Gleason scale, which is of considerable clinical significance. The application of the PI-RADS scale and collecting samples from areas with the score above 8 enabled detection of carcinoma in 91% of cases, including one potentially clinically relevant cancer and 2 clinically irrelevant diseases(.

Therefore, it might be concluded that the usage of three-dimensional imaging and monitoring biopsies enables more accurate staging of localized prostate carcinoma thanks to the detection of a greater number of pathological foci, including foci in localizations that are difficult to interpret during a conventional TRUS examination.