Prostate cancer is the most common cancer in males. It is estimated that about 60-70% of older men on autopsy have some degree of prostate cancer, compared with 15-20% of men diagnosed with prostate cancer during their lifetime and with the 3% lifetime risk of death from prostate cancer. 
Management of prostate cancer can include active surveillance, radiation therapy, cryotherapy, hormone therapy, and/or surgery. In active surveillance, patients are followed by their urologist by means of periodic physical exams, prostate-specific antigen (PSA) testing, digital rectal exam (DRE), and/or periodic repeat prostate biopsies. The decision regarding whether one can pursue active surveillance depends on the biopsy results, PSA levels, and the clinical stage of the cancer. The American Urological Association (AUA) deems active surveillance an option in prostate cancer patients who have a low PSA level, clinical stage, and Gleason score, making accurate biopsy results extremely important in considering patients for this option. 
A useful tool that can help supplement various diagnostic and treatment modalities for prostate cancer is transrectal ultrasonography (TRUS). TRUS has become an extension of the urologist’s finger in the early detection of prostate cancer. The evolution of end-firing probes has further enhanced urologists’ ability to monitor the entire process of a prostate biopsy.  TRUS is also widely used to deliver treatments such as brachytherapy and to monitor cryotherapy treatment for prostate cancer.
The use of sound waves to detect distant objects on the basis of their reflective properties became popular after World War II. In medicine, the initial use of ultrasound was in the detection of brain tumors. In urology, ultrasound was first used to detect renal stones during surgery.
The early applications of ultrasonography in medicine involved sound-wave generators, cathode-ray tubes, Polaroid photography, or 35-mm film recording. However, the invention of the silicone microchip gave birth to the modern ultrasonography revolution.
Early investigators in prostatic ultrasonography conducted experiments with ultrasound probes and recording devices. One of the earliest devices was a chair-type apparatus with a probe mounted in the center of the chair. The patient sat on the probe, which was guided into the rectum. Improvements in gray-scale ultrasound display and multiplanar scanning have resulted in user-friendly hand-held probes.
Earlier studies concentrated on the ultrasonographic appearances of prostate abnormalities such as benign prostatic hyperplasia (BPH), carcinoma of the prostate (CAP), prostatitis, prostatic abscess, and prostatic calculi. Since the introduction of the PSA screening test and early detection of prostate cancer, the role of TRUS has changed; it is mainly used to visualize the prostate (see the image below) and to aid in guided needle biopsy.
Real-time prostate biopsy has emerged as a potential replacement for conventional systematic biopsy in an effort to improve quality, reduce the number of clinically insignificant cancer diagnoses, and improve targeting of high-grade and clinically significant tumors.
The AUA has published updated guidelines for the early detection of prostate cancer (CAP) to guide urologists in the screening of asymptomatic men.  The panel recommended against screening men younger than 40 years and the routine screening of men aged 40 to 54 years who are at average risk for CAP. Men younger than 55 years who are at increased risk for CAP (family history or African American race) should discuss an individualized approach to prostate cancer screening with their urologists. Men aged 55 to 69 years appear to derive the greatest benefit from screening. For men in this age group, the panel strongly recommended shared decision-making regarding PSA screening and proceeding at 2-year intervals depending on the individual’s values and preferences. PSA screening is not recommended for men older than 70 years or for any man with less than 10-15 years of life expectancy. 
Possible future applications involving TRUS include the following:
Color Doppler scanning
Contrast-enhanced prostate biopsy
Intermittent and harmonic ultrasonography
High-intensity focused ultrasound (HIFU)
MRI ultrasound coregistration
Color Doppler scanning has been used to enhance the diagnosis of CAP as an adjunct to TRUS. Several investigators have demonstrated that the addition of color Doppler improved the specificity of prostate biopsy findings. However, differentiating a focus of prostatitis from cancer was difficult. The addition of power Doppler was not advantageous.
Contrast-enhanced prostate biopsy
The use of microbubble contrast agents can enhance gray-scale imaging and Doppler imaging. Newer agents that remain in the vascular compartment have been used for prostate imaging. Currently available agents include the following:
Perflenapent emulsion (EchoGen)
Galactose–palmitic acid (Levovist)
Perflexane lipid microspheres (Imavist)
Galactose suspension (Echovist)
Perflutren lipid microsphere (DMP 115, Definity)
Perfluorobutane microspheres (NC100-100, Sonazoid)
Several investigators have evaluated contrast-enhanced prostate ultrasonography. Ragde et al used EchoGen to study 15 patients with rising PSA levels and previous negative biopsy findings and found that the addition of this contrast agent helped guide biopsies to appropriate sites. 
Similarly, Watanabe et al studied 9 cases in which Levovist was used and demonstrated enhanced images of all cancers.  Halpern et al evaluated 26 patients with elevated PSA levels and found significant image enhancement after using Imavist.  However, the extra cost of this technique may be the limiting factor in its widespread use.
Intermittent and harmonic ultrasonography
The rationale for intermittent and harmonic ultrasonography is that conventional ultrasonography destroys the microbubbles of the contrast agents used in ultrasonographic imaging. Intermittent ultrasonography increases the enhancement provided by the contrast agents. In harmonic imaging, the reverberations produced by the contrast agent are visualized at a different frequency than the insonating frequency, which can provide a better image.
High-intensity focused ultrasound
With extracorporeal HIFU, temperatures higher than 60°C can be achieved in the target tissue. The prostate can be easily treated with this modality via a transrectal probe. The size of the thermal lesion can be controlled by the power and the duration of the ultrasound pulse. Higher in situ intensities (>3055 W/cm2) create the cavitation phenomenon and bubble effect, which are difficult to monitor.
The currently available HIFU devices use 3-4 MHz transducers. Experimental studies have shown core temperatures of 75°C, with a peak of 99°C during insonification.
Gelet et al pioneered the use of transrectal HIFU in the treatment of prostate cancer.  Currently, the procedure is used in Europe to treat localized prostate cancer and is performed with the patient under anesthesia and in a decubitus position. Rectal cooling is employed to prevent rectal burns.
Prostates smaller than 40 mL or those with an anteroposterior diameter of less than 5 cm are best suited for this treatment. During the procedure, the whole gland is treated (in contrast to focal therapy).
After the procedure, a suprapubic tube is left in place for 5-7 days. In a multicenter trial of 402 patients treated with HIFU, the median duration for catheter use was 5 days.  Prolonged retention occurred in 9% of patients, and 3.6% developed urethral strictures. Incontinence following HIFU was rare (0.6%). Rectourethral fistula developed in 1.2% of the patients.
Complication rates are higher with salvage HIFU after radiation therapy, radical prostatectomy, or HIFU. Erectile function can be preserved in 20-46% of patients who undergo only 1 session of HIFU.
After a minimum follow-up period of 6 months, Thuroff et al reported negative biopsy results in 87% of patients and a median nadir PSA level of 0.4 ng/mL after HIFU.  Gelet at al reported that 78% of low-risk patients were disease-free and had negative biopsy results at an actuarial 5-year follow-up. 
Gelet et al also reported salvage HIFU after failed radiation in 71 patients.  Among these patients, biopsy results were negative in 80%, and 61% had a PSA level nadir below 0.5 ng/mL. Complication rates after salvage HIFU were higher: total incontinence developed in 6%, rectourethral fistula in 6%, and vesical neck contracture in 17%.
DRE, PSA testing, and color Doppler TRUS-guided systematic biopsy are the basis for the diagnosis of prostate cancer. As alluded to earlier, TRUS has not been proven as a reliable imaging technique for localizing cancer foci within the prostate. Krouskop et al  theorized that cell density is greater in neoplastic tissue, causing a change in tissue elasticity. This line of thinking formed the basis for elastography, which was developed in the early 1990’s. As elastography developed, it has been increasingly applied for prostate cancer imaging. In 2005, Konig et al  studied 404 patients with suspected prostate cancer and found that elastography detected 84% of the 151 true positive cancer patients.
Elastrography is an ultrasound tool that is capable of mapping tissue stiffness of the prostate. There are 2 elastography techniques: quasi-static and shear-wave.  Quasi-static technique involves the analysis of prostate tissue deformation before and after compression by the ultrasound transducer. This difference in deformation is used to estimate the tissue stiffness. Reduced deformation typically indicates neoplastic tissue; additionally, if this tissue appears hypoechoic, it is likely a malignancy. The shear-wave technique requires no compression of the rectal wall and is based on the measurement of shear-wave velocity propagating through the tissues. Elastic properties are typically provided in kilopascals (kPa), where neoplastic nodularity is suspicious at levels greater than 35 kPa. 
Elastography has proved to be a useful tool in the detection of prostate cancer. In 2005, Konig et al  studied 404 patients with suspected prostate cancer and found that elastography detected 84% of the 151 true positive cancer patients. In Miyanaga’s 2006 study,  of 29 patients with untreated prostate cancer, the sensitivity of elastography, TRUS, and DRE were 93%, 59%, and 55%, respectively. Pallwein et al  studied 15 patients who were initially studied with standard ultrasound and elastography before undergoing robot-assisted laparoscopic prostatectomy, and they found that elastography was 88% sensitive for detecting cancer foci and that 78.3% of the cases correlated with the histologic findings. Further analysis showed that the best sensitivity and specificity were found in the apex region. Additionally, elastography has ben shown to have a negative predictive value of up to 99% for the detection of prostate cancer, making it unlikely that cancers will be missed with this technique. 
In terms of targeted prostate biopsy, a larger study, by Pallwein et al,  concluded that elastography was 2.9 times more likely to detect prostate cancer than systematic TRUS biopsy. Furthermore, elastography required fewer than half the number of biopsy cores. When evaluating elastography for the staging of prostate cancer, Salomon et al  evaluated 15 patients who underwent elastography after radical prostatectomy and found that 14 of 15 patients were correctly identified for the presence or absence of extracapsular disease.
Elastography certainly has shown promise as an alternative to conventional TRUS, and further clinical trials are currently being conducted, which will likely lead to better understanding of the exact role for elastography in the management of prostate cancer.
MRI ultrasound coregistration
Prostate MRI was first reported over 30 years ago.  MRI "in bore" biopsy, where targeting biopsies are performed within the MRI gantry, has been the most widely examined prostate biopsy procedure; however, because of increased cost, lack of availability, and overall clinical outcomes, it is unlikely to replace systematic biopsy. MRI coregistration with ultrasound, commonly referred to as MR-US fusion, has been an area of increasing research and is a potential replacement for systematic biopsy moving forward.
MR-US fusion allows MRI data to be used to obtain biopsies under ultrasound guidance. Cognitive fusion refers to the operator viewing lesions on MRI, allowing one to attempt biopsy of the visualized location from memory using real-time US. Obvious disadvantages include potential for human error and the steep learning curve and variability of results. In an effort to reduce this variability, several fusion devices have been developed and are now approved by the FDA.
The Artemis device (Eigen) utilizes tracking of the TRUS probe by a directly attached robotic arm that translates the 2D US into a 3D model, which is fused with the preprocedure MRI and allows targeting of suspicious lesions.  The device also tracks biopsy sites, allowing rebiopsy of the exact site at a later time.
Sonn et al  found that in men undergoing active surveillance with previously negative biopsy results, the Artemis device detected cancer in 55% of men overall and 94% of those with the highest level of suspicion on MRI. They also found that there was a clinically significant increase in the detection of significant cancers and a decreased detection of insignificant cancers, as compared to systematic biopsy.
Disadvantages of using the Artemis device include the bulkiness of the device and difficulty with in-office use. The UroNav device (Invivo) utilizes a sensor that attaches to the TRUS probe, and using a small electromagnetic field placed in close proximity to the patient, it fuses the MRI data.  It is a free-hand technique that is generally more familiar to urologists. However, it has the disadvantage of an electromagnetic field, as opposed to the accuracy of the robot.
Vourganti et al  found that in patients with previous negative biopsy results, UroNav detected cancer in 37% of patients, including 11% with high-grade disease. The Urostation device (Koelis) utilizes real-time 3D TRUS in a recreated model of the prostate to localize each biopsy site.  The model is reset with each probe firing to adjust for any changes. This device has the advantage of a free-hand platform, though the inherent error in any free-hand technique still exists.
Delongchamps et al  compared cognitive and fusion MR-US devices with systematic biopsy. In their study of 391 patients, they found no difference in the rate of cancer detection for visually targeted versus random biopsy. The fusion MR-US devices did increase the detection of high-grade cancer with fewer cores, while decreasing the rate of micro focal cancer detection.
Puech et al  studied men with a suspicious lesion on MRI, and each man underwent 12 random core biopsies, 2 visually guided biopsies, and 2 MR-US fusion software-targeted biopsies. The study found that targeted biopsy detected clinically significant cancer in more men than random biopsy; however, there was no significant difference in cancer detection between cognitive fusion and MR-US fusion software.
MR-US coregistration has shown promise as a targeted method of sampling the prostate leading to more accurate identification of clinically significant prostate cancer. However, it remains unclear whether the biopsy results can be applied to the conventional risk-stratification systems that were designed for systematic and random biopsy. It is also unclear how exactly this will impact the practicing urologist. Long-term studies are certainly required. Nonetheless, it is an important advancement in the ongoing effort to improve the management of prostate cancer.
The AUA and Society of Abdominal Radiology (SAR) has issued a consensus statement on the role of MRI in prostate biopsies.  The joint commission recognizes that the use of prostate MRI followed by MRI-targeted core biopsy is more useful in detecting clinically significant disease over standardized repeat biopsy. As a result, the organizations recommend that physicians strongly consider prostate MRI in patients with a prior negative biopsy who are undergoing repeat biopsy for clinically suspicious cancer. The authors state that the MRI should be reported in accordance with the Prostate Imaging rRporting and Data System (PI-RADS) version 2 (V2) guidelines. In these guidelines, each lesion is assessed a number (1-5) on the basis of the likelihood of the lesion correlating with the presence of cancer (see Table 1).  The committee recommends image-targeted biopsy for any lesions with a PI-RADS category of 3 to 5.
The recommendations also note that although TRUS-MRI fusion and in-bore MRI targeting biopsies may be useful for smaller lesions, cognitive fusion will suffice if this equipment is not readily available. During the procedure, it is recommended that at least 2 targeted cores be taken from each suspected lesion, although this number could vary on the basis of the specific case and the physician’s clinical judgment. Furthermore, in patients with negative or lower-suspicion MRI findings, ancillary tests (eg, PSA, PSAD) may be helpful in determining which patients warrant rebiopsy.
Table. (Open Table in a new window)
|Table 1. PI-RADS Assessment Categories|
|Assessment categories||Likelihood for cancer|
TRUS has both diagnostic and therapeutic indications. Diagnostic indications for TRUS include early diagnosis of CAP. However, ultrasonographic findings alone cannot be used to establish or exclude the diagnosis of CAP: definitive diagnosis must be based on biopsy results, along with abnormal DRE findings, elevated PSA levels, or both.
TRUS is also used diagnostically to determine the volume of the prostate gland and thereby facilitate the planning of brachytherapy, cryotherapy, or minimally invasive BPH therapy (eg, radiofrequency or microwave therapy). In addition, TRUS is used to evaluate prostate volume during hormonal downsizing for brachytherapy. Finally, TRUS is used in the evaluation of men with azoospermia to rule out ejaculatory-duct cysts, seminal vesicular cysts, müllerian cysts, or utricular cysts.
Therapeutic indications for TRUS include the following:
Brachytherapy for CAP
Cryotherapy for CAP
Deroofing or aspiration of ejaculatory ducts, prostatic cysts, or prostatic abscesses
Contraindications for TRUS-guided biopsy of the prostate include an acute painful perianal disorder and a hemorrhagic diathesis. As a rule, patients should be discouraged from taking aspirin or nonsteroidal anti-inflammatory drugs for at least 10 days before the procedure, but recent use of these agents should not be considered an absolute contraindication for prostate biopsy.
The adult prostate is a chestnut-shaped organ enveloped in a fibrous capsule. The base of the prostate is attached to the bladder neck, and the apex is fixed to the urogenital diaphragm. The prostatic urethra traverses the gland. The verumontanum is a longitudinal ridge in the prostatic apex onto which the ejaculatory ducts open.
The prostate is located superior and posterior to the seminal vesicles. The ampullae of the vas deferens run medial to the seminal vesicles along the posterior surface of the prostate. Anteriorly, the fibrous capsule thickens at the level of the apex to form puboprostatic ligaments, which attach the prostate to the back of the symphysis pubis.
The dorsal venous complex (ie, the Santorini plexus) runs along the puboprostatic ligaments. The prostate gland lies beneath the endopelvic fascia. Posteriorly, the 2 layers of Denonvilliers fascia separate the prostate from the rectum. The rectourethralis muscle attaches the rectum to the prostatic apex.
A rich plexus of veins encompasses the prostate gland between the true fibrous capsule of the gland and the lateral prostatic fascia; these are visible landmarks on sonograms (see the image below). The neurovascular bundles run craniocaudally along the posterolateral aspects of the prostate. The prostate gland is supplied by the prostatic artery, which is usually a branch of the inferior vesical artery. The prostatic artery divides into a urethral branch, which supplies the transition zone, and a capsular branch.
Venous drainage from the prostate moves into the Santorini plexus and eventually into the internal iliac vein. The prostatic venous plexus communicates freely with the extradural venous plexus (ie, the Batson plexus), and this communication is thought to be a factor in the spread of prostate cancer. Initially, lymphatic drainage of the prostate is into the obturator lymph nodes and into the hypogastric chain.
The nerve supply to the prostate is both sympathetic, from the hypogastric plexus (L1-2), and parasympathetic, from the pelvic nerve (nervi erigentes, S2-S4). Although the cavernous nerves run along the posterior aspect of the prostate, the 2 distinct areas from which prostatic nerves leave the gland are thought to be the superior and inferior pedicles. These areas are the first sites of extraprostatic spread of cancer.
According to the classic work by McNeal, the prostatic urethra, which is the main reference point of the prostate, divides the gland into an anterior fibromuscular stroma and a posterior glandular organ. The urethra is angled 35° anteriorly in the proximal portion of the prostate. The ejaculatory ducts run in the same plane as the distal prostatic urethra to join the verumontanum.
Lowsley’s concept of a 5-lobed prostate has been replaced by McNeal’s concept of zonal architecture. In this scheme, the prostate has 4 glandular zones, each with its own ductal system. The peripheral zone, the transition zone, and the periurethral glands have a similar histologic appearance and are derived from the urogenital sinus. However, the central zone is histologically distinct from the other 3 zones and is derived from mesonephric tissues (ie, wolffian tissue).
The peripheral zone constitutes almost 75% of the normal prostate gland. It occupies the distal prostate gland, the area around the urethra distal to the verumontanum. The acini are small, round, and smooth-walled, and their ducts drain into the urethra distal to the verumontanum. The stroma is loosely woven with randomly oriented muscle fibers. Approximately 70% of CAP cases arise in this zone.
The central zone constitutes 25% of the normal prostate and occupies the part of the prostate behind the proximal prostatic urethra. The ejaculatory ducts pass through the central zone. The acini are large and irregular, with significant intraluminal folds and ridges. They are also surrounded by muscular tissue that closely follows the shape of the acini. Approximately 5-10% of CAP cases arise in this zone.
The transition zone makes up approximately 5-10% of the normal prostate gland (see the image below). The transition zone lies on either side of the proximal prostatic urethra, lateral to the internal sphincter. The glandular architecture is similar to that of the peripheral zone; however, the stroma is more compact. The transition zone is where BPH originates and where approximately 20% of CAP cases arise.
The periurethral glands make up less than 1% of the glandular tissue. These glands are embedded in the smooth muscle of the prostatic sphincter. This is the site of origin of the large median lobe of BPH.
Anterior fibromuscular stroma
The anterior part of the prostate is composed mainly of fibromuscular stroma, which is continuous with detrusor fibers. Toward the apex of the gland, this fibromuscular tissue blends with striated muscle from the levator. Puboprostatic ligaments also blend with this area.
Invaginated extraprostatic space
As the ejaculatory ducts enter the prostate posteriorly, an invaginated extraprostatic space (IES) surrounds them and invaginates into the prostate. The IES surrounds the ejaculatory ducts, ends at the verumontanum, and communicates with the periurethral space.
In 1989, Lee introduced the concept that invasion of the IES may be the first sign of extraprostatic extension of prostate cancer and an early sign of invasion of seminal vesicles. In 2005, Amin et al evaluated the pathological significance of the invasion of IES in 80 patients with prostate cancer and concluded that IES involvement was consistently seen in cases with seminal vesicle invasion. 
Bladder neck and internal sphincter
The internal sphincter runs from the bladder neck to the level of the verumontanum. The smooth muscle fibers of the sphincter are continuous with the superficial layer of the trigone. In healthy males, the bladder neck and the internal sphincter are closed. In males with a neurogenic bladder, the bladder neck and the prostatic urethra are wide open, and some investigators have used TRUS to monitor the lower urinary tract in patients with spinal injuries.
Gill and Ukimura, in a study reporting on the use of TRUS monitoring with Doppler during laparoscopic radical prostatectomy to identify the blood flow in the neurovascular bundles, found that identification and preservation of pulsatile blood vessels within these bundles resulted in superior recovery of erectile activity postoperatively. 
More than 80% of urologists administer an enema before TRUS and prostate biopsy. However, some authors consider this practice unnecessary.
More than 90% of urologists administer prophylactic oral antibiotics. Reported regimens include a total of 11 different antibiotics, with 20 different dosages and treatment durations ranging from 1 to 17 days.
There is increasing support for a simpler prophylactic regimen in patients with uncomplicated medical conditions. The protocol most commonly recommended consists of 2 doses of a fluoroquinolone, with the first given before the procedure and the second 12 hours later. Targeted antimicrobial prophylaxis has been employed in cases of infections caused by fluoroquinolone-resistant organisms. 
In patients with prosthetic implants or valvular heart disease, additional prophylaxis with ampicillin 1 g intramuscularly (IM)—or, in penicillin-allergic patients, vancomycin 1 g intravenously (IV)—plus gentamicin 80 mg IM is recommended.