Balkan Military Medical Review Oct - Dec 2013; 16(4): 441 - 448 Review Article Contemporary Role of Transrectal Ultrasound - Guided Prostate Biopsy Ioannis GALANAKIS1, Eleftherios AGIANNIOTAKIS2, Stylianos MEGREMIS3, Georgios DELIMPASIS4, Konstantinos PSARAS5, Anastasios GIFTOPOULOS4, Konstantinos PSILLAKIS6, Ioannis PETINARAKIS2, Ilias PALAIODIMOS7, Christos BISSIAS8* Affiliation of the authors: 1. MD, PhD, FEBU, Department of Urology, Naval Hospital of Athens 2. MD, Department of Radiology, Sitia District General Hospital, Crete 3. MD, PhD, 1st Department of Radiology, Venizeleion Hospital, Crete 4. MD, Department of Radiology, 251 Hellenic AirForce Hospital, Athens 5. MD, Aegean Imaging, Rhodes 6. MD, 1st Department of Radiology, Venizeleion Hospital, Crete 7. MD, Department of Urology, Sitia District General Hospital, Crete 8. MD, 1st Department of Orthopaedics, Naval Hospital of Athens Corresponding author: Dr Ioannis GALANAKIS, MD, PhD, FEBU Naval Hospital of Athens Deinokratous Str, 70 11521 - Athens Tel: 0030 210 7261333 E-mail: [email protected] 442 Abstract Prostate cancer is by far the most common solid neoplasm in male population, in Europe and USA, nowadays. The only accurate method to establish the diagnosis is the biopsy of the prostate or the presence of cancer in prostatectomy specimen. Prostate biopsy is usually performed using transrectal ultrasound (TRUS) which has gone through various modifications over the years and is considered now as the gold standard for prostate biopsy. However, a lot of unnecessary biopsies are performed and a lot of insignificant cancers are identified every day. "When to biopsy" is a rather puzzling issue. This article aims to review the current indications and techniques of TRUS guided prostate biopsy. Key words: prostate cancer, biopsy, transrectal ultrasound Introduction Prostate cancer (PCa) is recognized, nowadays, as one of the most important medical problems facing the male population. In Europe, PCa is by far the most common solid neoplasm with an incidence rate of 214 cases per 1000 men and it is the second most common cause of death in men [1, 2]. The etiology of PCa is not well known and many risk factors have been studied; however only three of them have been well-established: increasing age, heredity (if one first-line relative has PCa, the risk is doubled and if two or more firstline relatives are affected, the risk increases by 5- to 11-fold), ethnic origin (African and African Caribbean men are three times more likely to develop prostate Balkan Military Medical Review Vol. 16, No 4, Oct - Dec 2013 cancer than white men of the same age) [1, 2]. Digital rectal examination (DRE), Prostate-specific antigen (PSA) and Transrectal Ultrasonography (TRUS) are the main diagnostic tools to obtain evidence of PCa and to perform, in consequence, prostate biopsy which definitely confirms the presence of cancer. This article aims to review the current indications and techniques of TRUS-guided prostate biopsy. Prostate Anatomy The prostate gland (Fig. 1) is about the size of a walnut and surrounds the neck of a man’s bladder and urethra. It measures about 4 cm transversely at the base, 2 cm in its antero-posterior diameter, and 3 cm in its vertical diameter, with a mean volume of 20ml. The prostate is immediately enveloped by a thin but firm fibrous capsule, distinct from that derived from the fascia endopelvica and separated from it by a plexus of veins. This capsule firmly adheres to the prostate and is structurally continuous with the stroma of the gland. Figure 1. Sagittal view of the prostate Galanakis I. et al: Contemporary Role of Transrectal Ultrasound - Guided Prostate Biopsy The prostate can be divided in two ways: by zone or by lobe. McNeal was the first to propose in 1968 that a prostate consists of three zones: transitional, central, peripheral and the anterior fibromuscular stroma , (Fig. 2). The zone classification is most often used in pathology while the lobe classification (anterior, posterior, middle and lateral lobes) is used in anatomy. Up to 70-80% of prostatic cancers originate from the peripheral zone, 10-20% from the transitional and only 2.5% originate from the central zone. Figure 2. Schematic depiction of the transition zone (TZ), central zone (CZ) and peripheral zone (PZ) in transverse (A) and sagittal (B) planes. The arrows represent the path of sextant biopsy needles The seminal vesicles (SVs) are a pair of small tubular glands located posterior to the bladder and distal ureters. The SV joins the distal portion of the vas deference (VD) and becomes the ejaculatory duct (ED), which drains into 443 the prostatic urethra through the verumontanum. The arteries supplying the prostate are derived from the internal pudendal, inferior vesical and middle hemorrhoidal artery. The prostatic venous plexus drains into the internal iliac veins and communicates with the vertebral plexus, thereby allowing neoplastic spread to the vertebrae. The lymphatics end mostly in the internal iliac nodes, although some end in the external iliac nodes. The nerves are derived from the pelvic plexus. Trus technique There are several variations in the technique of the TRUS-guided prostate biopsy. We present here the most widely accepted: Patient preparation: fully informed consent that outlines alternatives, consequences and complications of biopsy is obtained prior to the procedure. A fiveday course of oral fluorokinolone is required, starting the previous day. The patient is advised to take a selfadministered cleansing enema (sodium phosphate and dibasic sodium phosphate) prior to the biopsy to eliminate gas and remove feces. Patients on anticoagulation therapy, aspirin or non-steroidal antiinflammatory (NSAIDS) agents are advised to stop or adjust their treatment depending on the agent. Transrectal ultrasound: the patient is positioned in the left lateral decubitus position so as the probe can be inserted more easily to the rectum. A topical anesthetic ointment is applied to the index finger prior to performing the DRE. A 5.0 to 7.5 mHz transducer is used for transrectal imaging of the prostate. The probe is gently advanced into the rectum and transverse images are then obtained as the probe is moved back from the base to the apex. The volume of the prostate can be calculated assuming that the gland is an 444 ellipsoid. Thus, the formula for the prostate’s volume is: (transverse diameter) × (cephalo-caudal diameter) × (anteriorposterior diameter) × (0.52). The normal prostate gland has a homogenous, uniform echo pattern. The most common finding of prostate cancer in TRUS is a hypoechoic area in the peripheral zone with a sensitivity of 82%, specificity of 24%, positive predictive value of 23%, negative predictive value of 88% and overall accuracy of 40% (Fig. 3). The prevalence of isoechoic or nearly invisible prostate cancers on TRUS ranges from 22 to 38%. European Association of Urology (EAU) guidelines recommend not to replace systematic with targeted biopsies of suspect areas . However, additional biopsies of suspect areas may be useful . Figure 3. Transrectal ultrasonography. Top image, solid white arrow depicts hypoechoic lesion within the peripheral zone concerning prostate cancer. Lower image depicts hypervascular area seen with color Doppler imaging, yellow and red area corresponds to the hypoechoic area seen on the grayscale ultrasonography above. Biopsy technique: An 18-gauge biopsy needle loaded in a spring-action Balkan Military Medical Review Vol. 16, No 4, Oct - Dec 2013 automatic biopsy device is commonly used to procure multiple 1.5cm prostate biopsy specimens. The sextant biopsies scheme from the mid lobe (parasagittal) of each side of the prostate at the apex, middle, and base, proposed by Hodge et al, was the standard of care for many years , (Fig. 2). However, it was the time when most cancers were palpable on DRE. In the current PSA era, most cancers are NOT! Furthermore, mapping of radical prostatectomy specimens has shown that the majority of non palpable lesions lie in the far lateral peripheral zone of the prostate, which is not routinely sampled by the sextant technique. Many authors evaluated various biopsy strategies with extended sampling cores, however the optimum has not yet been determined. The EAU recommends: "Sextant biopsy is no longer considered adequate. At a glandular volume of 30-40 ml, at least eight cores should be sampled. The British Prostate Testing for Cancer and Treatment Study has recommended 10 core biopsies. More than 12 cores are not significantly more conclusive" . Larger prostate volumes need an individualized core strategy. A recommended scheme for initial prostate biopsy is shown on Fig. 4. Galanakis I. et al: Contemporary Role of Transrectal Ultrasound - Guided Prostate Biopsy Figure 4. Recommended scheme for initial prostate biopsy. A lateral and medial sextant pattern with 12 cores (extended) covers the entire peripheral zone (PZ) of the prostate to maximise diagnosis of the most frequent cancer located in the PZ. Anesthesia for prostate biopsy: The minimum is the application of rectal lidocaine gel 2% for 10 min before the procedure. This should be combined with a diclofenac 100 mg suppository 1 hour before biopsy. However, the EAU recommends: "Ultrasound-guided periprostatic block is state-of-the-art. It does not make any difference whether the depot is apical or basal. Intrarectal instillation of a local anesthetic is clearly inferior to periprostatic infiltration" . 10–20 mls of local anesthetic is adequate. For prostate biopsies with high number of samples (saturation biopsy), a spinal or general anesthesia is useful. General indications for prostate biopsy A) Level of PSA The first elevated PSA level should not prompt an immediate biopsy. It needs to be verified after a few weeks by the same assay under standardized conditions (no ejaculation and no manipulations, such as catheterization, cystoscopy, transurethral resection and no urinary tract infections) . There is no normal value for PSA; 25% of cancers are detected in the zone 04ng/ml. Stamey et al in 1987 found 5.5% cancer in patients with PSA 4-10ng/ml and normal DRE . Recent studies found 2030%! It is widely accepted that PSA>4ng/ml is a strong indication for a biopsy. However, many experts suggest that the cut-off should be 2.5ng/ml, taking into consideration recent studies (Catalona, Smith) who found raised prostate cancer rates in the PSA zone of 2.5-4ng/ml, with 80% of them being aggressive! [7, 8] 445 B) Positive DRE Jewet et al found that 50% of patients with a positive DRE have prostate cancer. Schroder et al, however, showed in 1998 that DRE has low prognostic value and since then the European Randomized Study of Screening for Prostate Cancer does not recommend DRE as a screening tool . Nevertheless, DRE remains a routine examination in all centers! C) High Grade Prostatic Intraepithelial Neoplasia (HGPIN) In earlier studies, 25-79% of patients with HGPIN had prostate cancer on repeat biopsy. More recent studies though, where the extended core technique was used, showed much lower results (2.54.3%). As a conclusion, HGPIN as an isolated finding is no longer considered an indication for repeat biopsy . If PIN is extensive (i.e. in multiple biopsy sites), this could be a reason for early repeat biopsy because the risk of subsequent PCa is slightly increased . D) Atypical Small Acinar Proliferation (ASAP) ASAP is a different entity than HGPIN, rather aggressive, found in 0.523% in prostate biopsies. In the presence of ASAP, a repeat biopsy will reveal cancer in 36-49%! Iszkowski et al proposed repeat biopsies with 3-12 months intervals . Relative Indications for Prostate Biopsy A) Palpable abnormality or/and rising PSA after definitive treatment Many authors suggest that a palpable abnormality or/and rising PSA after definitive treatment (radical prostatectomy, radiotherapy, cryotherapy) is a relative indication for a prostate biopsy in order to exclude local recurrence. 446 B) PSA elevation related to age Oesterling et al evaluated 2119 healthy men aged 40 to 79 years, in a prospective, community-based study and concluded that the serum PSA concentration is directly correlated with patient age and prostatic volume, the latter of which is also directly related to age . Thus, rather than rely on a single reference range for men of all age groups, it is more appropriate to have age-specific reference ranges. These agespecific reference ranges have the potential to make serum PSA a more discriminating tumor marker for detecting clinically significant cancers in older men (increasing specificity) and to find more potentially curable cancers in younger men (increasing sensitivity): 40 to 49 years — 0 to 2.5 ng/mL 50 to 59 years — 0 to 3.5 ng/mL 60 to 69 years — 0 to 4.5 ng/mL 70 to 79 years — 0 to 6.5 ng/mL C) PSA velocity Some authors have suggested that assessing changes in PSA over time (PSA velocity) may improve the accuracy of aggressive prostate cancer detection when compared to a single measurement of PSA alone . It has been proposed that a PSA rise of 0.75 ng/ml or greater may be related to cancer in patients with a PSA between 4 and 10ng/ml, while a PSA velocity threshold of 0.4ng/ml has been proposed for younger men with baseline levels <4ng/ml. D) Free/total PSA ratio (f/t PSA) The free/total PSA ratio (f/t PSA) is used to stratify the risk of PCa for men who have total PSA levels between 4 and 10ng/ml and a negative DRE. In a prospective multicentre trial, PCa was found on biopsy in 56% of men with f/t PSA < 0.10, but in only 8% of men with f/t PSA > 0.25 [4, 14]. Nevertheless, the concept must be used with caution as Balkan Military Medical Review Vol. 16, No 4, Oct - Dec 2013 several pre-analytical and clinical factors may influence the f/t PSA, e.g. instability of free PSA, variable assay characteristics and very large prostate size. For example, free PSA is unstable at both 4°C and at room temperature. In addition, assay characteristics may vary and concomitant Benign Prostatic Hyperplasia (BPH) in large prostates may result in a dilution effect. Furthermore, f/t PSA is of no clinical use in total serum PSA values > 10 ng/mL or during follow-up of patients with known PCa [4, 15, 16]. E) PSA density Less commonly agreed upon recommendation for TRUS guided prostate needle biopsy includes PSA density (PSAD) > 0.15, which is a measure of the amount of PSA relative to the overall prostatic volume (PSA / Prostate Volume in cubic centimeters). It must be emphasized that there is no consensus on using any of the PSA modifications and none of them has been shown in clinical trials to reduce the number of unnecessary biopsies or improve clinical outcomes. The total PSA cutoff of 4.0 ng/ml has been the most accepted standard because it balances the trade-off between missing important cancers at a curable stage and avoiding both detection of clinically insignificant disease and subjecting men to unnecessary prostate biopsies. Ongoing efforts are targeted at identifying new serum markers that will have greater diagnostic accuracy for prostate cancer, particularly for aggressive tumors. Special Considerations Transition zone biopsy Transition zone (TZ) sampling during baseline biopsies provides a very low detection rate and TZ sampling should Galanakis I. et al: Contemporary Role of Transrectal Ultrasound - Guided Prostate Biopsy therefore be confined to repeat biopsies . Seminal vesicle biopsy Indications for SV (staging) biopsies are poorly defined. At PSA levels >15-20 ng/mL, the odds of tumor involvement are 20-25%, but a biopsy is only useful if the outcome will have a decisive impact on treatment, i.e. if the biopsy result rules out radical removal for tumor involvement or radiotherapy with intent to cure . Saturation biopsy The incidence of PCa detected by saturation repeat biopsy (>20 cores) is between 30% and 43% and depends on the number of cores sampled during earlier biopsies . The high rate of urinary retention (10%) is a drawback. Transperineal biopsy The standard of care to perform a prostate biopsy is the transrectal approach. However, some urologists prefer to use a perineal approach with comparable cancer detection rates. The prostate is accessed with the tru-cut biopsy needle through a small incision of the perineum about 2cm above the anal verge with the ultrasound probe in the perineum. The ultrasound-guided perineal approach is a useful alternative in special situations, e.g. after rectal amputation. Complications of prostate biopsy TRUS-guided prostate needle biopsy is generally a safe procedure. It is associated with frequent minor (range 60% to 79%) and rare major (range 0.4% to 4.3%) complications and the need for hospitalization ranges from 0.4% to 3.4%. Persistent hematuria is the most common complication and occurs in 47.1% of patients and typically lasts 3 to 7 days following the biopsy. Other complications 447 of TRUS-guided prostate biopsy include: vasovagal episodes (5.3%), dysouria (9.1%), prostatitis (1.0%), hematospermia (37.4%), rectal bleeding (8.3%), urinary retention (0.2%), fever>38.5oC (0.8%). Conclusions Ferguson was the first to perform a prostate needle biopsy using a transperineal approach in 1930 while Astraldi used a transrectal approach in 1937. However, it was in 1987 when an ultrasound probe was used to optimize the transrectal prostate biopsy. Since then, as ultrasound technology has become more refined, this technique has been described as a superior method of performing a core biopsy of the prostate. The optimum regimen for the diagnosis of prostate cancer remains to be determined. The ideal place and number of cores are not clear but recent data support the use of extended biopsy schemes. 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