Key points

Introduction

Prostate cancer (PCa) is the most common neoplasm in the Western hemisphere, and the incidence is still increasing. Screening, detection, and diagnosis of PCa are currently based on serum prostate-specific antigen (PSA) level; digital rectal examination (DRE) and transrectal ultrasound (TRUS)-guided systemic biopsies. Although there is intense controversy concerning PCa screening, when a decision is made to perform a diagnostic prostate biopsy (PB), TRUS is the preferred and standard-of-care technique.

TRUS has many advantages over other medical imaging modalities. The lack of ionizing radiation, low cost, and the proximity of the prostate to the rectal wall resulted in TRUS being the most commonly used prostate imaging modality. After the initial introduction of the sextant PB technique proposed by Hodge, little refinement of the technique was carried out until Stamey suggested directing the biopsies more laterally. It was then recognized that even lateral sextant biopsies could miss up to 30% of cancers, because more extended biopsy schemes result in higher cancer detection rates. As defined by the National Comprehensive Cancer Network (NCCN), an extended PB (EPB) is essentially a sextant template with at least 4 additional cores from the lateral peripheral zones as well as biopsies directed to lesions found on palpation or imaging. Little controversy exists in the urologic community regarding the usefulness of EPB compared with sextant biopsy in increasing the detection rate of PCa.

Introduction

Prostate cancer (PCa) is the most common neoplasm in the Western hemisphere, and the incidence is still increasing. Screening, detection, and diagnosis of PCa are currently based on serum prostate-specific antigen (PSA) level; digital rectal examination (DRE) and transrectal ultrasound (TRUS)-guided systemic biopsies. Although there is intense controversy concerning PCa screening, when a decision is made to perform a diagnostic prostate biopsy (PB), TRUS is the preferred and standard-of-care technique.

TRUS has many advantages over other medical imaging modalities. The lack of ionizing radiation, low cost, and the proximity of the prostate to the rectal wall resulted in TRUS being the most commonly used prostate imaging modality. After the initial introduction of the sextant PB technique proposed by Hodge, little refinement of the technique was carried out until Stamey suggested directing the biopsies more laterally. It was then recognized that even lateral sextant biopsies could miss up to 30% of cancers, because more extended biopsy schemes result in higher cancer detection rates. As defined by the National Comprehensive Cancer Network (NCCN), an extended PB (EPB) is essentially a sextant template with at least 4 additional cores from the lateral peripheral zones as well as biopsies directed to lesions found on palpation or imaging. Little controversy exists in the urologic community regarding the usefulness of EPB compared with sextant biopsy in increasing the detection rate of PCa.

Indications

PB is indicated when there is suspicion of advanced or metastatic PCa based on factors such as bony metastasis or pelvic/retroperitoneal adenopathy or suggestive symptoms. More commonly, the decision to perform PB has been traditionally based on abnormal DRE or increased PSA level. Abnormal DRE usually indicates an initial PB irrespective of PSA level. In the Washington PCa screening study, 14% of the cancers were diagnosed by DRE alone. Among those patients who underwent radical prostatectomy (RP) based on abnormal DRE, 20% were non–organ confined and 20% had a Gleason score of 7 or greater.

The debate regarding the pros and cons of PSA-based screening continues and is beyond the scope of this review. If a patient opts for PSA-based screening, there is no absolute cutoff for PB ( Table 1 ). Most sources recommend repeating an abnormal PSA value before making the decision to perform PB with a normal DRE, and there is general agreement that PSA higher than 4 is suggestive of the presence of PCa for a biopsy. A PSA threshold of 2.6 ng/mL doubles cancer detection rates in men younger than 60 years with little loss in specificity. There are several other factors to consider in proceeding to biopsy, potentially including PSA velocity, % free PSA, PSA density (PSAD), age, family history, ethnicity, and comorbidities. The NCCN recommends the use of a PSA velocity of 0.35 ng/mL/y or greater as indication for biopsy in men with PSA 2.5 ng/mL or less. In addition, the group recommends the use of % free PSA as alternative indication of initial biopsy, with the intention of avoiding unnecessary biopsies. The % free/total PSA ratio can be used to indicate biopsy if less than 10%, consider PB intermediate if between 10% and 25%, and no PB if greater than 25%. PSAD and age-referenced PSA have been investigated but are controversial. Recent data from the dutasteride REDUCE (reduction by dutasteride of prostate cancer events) chemoprevention trial again confirmed that family history is a significant risk factor for cancer. Several researchers found that African American race remains an independent predictor of PCa detection in men undergoing initial PB.

Newer tests such as kallikrein markers in blood, genomics, proteomics, and a variety of urinary markers such as PCA3 and TMPRSS2-ERG remain under investigation to aid in the decision making for PB. Box 1 lists the factors to be considered as an indication for PB.

Predictive models have been developed to reduce unnecessary biopsies and still detect most clinically important cancers and are available on the Internet. The finasteride-based PCa Prevention Trial model ( http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp ) uses variables such as PSA, age, family history, race, DRE, and previous negative biopsy. The European Randomized Study of Screening for PCa (ERSPC)-based model has several calculators ( http://www.prostatecancer-riskcalculator.com/ ) that rely on additional items such as TRUS-estimated prostate volume and the presence of hypoechoic lesions. Other indications for PB include as a part of an active surveillance (AS) protocol and in the evaluation of recurrence after local radiation therapy.

Patient preparation

A complete history and physical examination, urinalysis and culture, and PSA determination are mandatory before a PB. Attention to any anorectal disease that may interfere with the probe or needle insertion should be noted. The use of low-dose aspirin does not seem to increase bleeding and should be continued if deemed medically necessary. Oral anticoagulants should be stopped 5 days before the biopsy and low-molecular-weight heparin bridging used if medically indicated.

The use of rectal enema to reduce infectious complications is contentious, with 81% of urologists in the United States using an enema in preparation for a TRUS biopsy. Several studies showed that the risk of infectious complications is lower if a rectal enema is used. In a large study from Korea, infectious complications developed in 1.3% of patients who had rectal preparation, but in 9.5% of those who did not. In another nonrandomized Korean study, the use of a povidone-iodine suppository before biopsy markedly reduced infectious complications.

However, a study by Carey and Korman reported that enema before biopsy provides no significant advantage in clinical outcome. Moreover, in a recent study from Canada, rectal cleansing with povidone-iodine before TRUS biopsy did not significantly reduce the risk of infectious complications. Box 2 lists the factors to consider before a PB.

Antibiotic prophylaxis

Infectious complications associated with TRUS biopsies are a growing concern. More frequent complications are being observed, and the rate of resistance to commonly used antibiotics is increasing. Infectious complications related to TRUS biopsy range from transient fever to urinary tract infection (UTI), sepsis, and possible death. The rate of sepsis after TRUS biopsy is estimated to be between 0.1% and 5%, with UTIs occurring in 3% to 11% of patients. The standard of care is to use antibiotics at the time of TRUS biopsy. Traditionally, fluoroquinolones have been used. In a survey of more than 900 US urologists, more than 85% reported using fluoroquinolones. There is no evidence whether a single or a more extended protocol is needed. Recent studies suggest that the escalating rates of infectious complications and need for hospitalization are often caused by fluoroquinolone-resistant bacteria. Two antibiotic prophylactic strategies are being used ( Box 3 ). Studies have shown reduced risk of infection in patients by adding a single dose of aminoglycoside just before biopsy. Another proposed strategy is the use of rectal swabs before TRUS biopsy to screen patients for colonization with fluoroquinolone-resistant bacteria and then to use targeted antimicrobial prophylaxis. The antibiotics for PB recommended by the American Urological Association (AUA) include fluoroquinolones or first-generation/second-generation/third-generation cephalosporins.

Alternatively, aminoglycoside or aztreonam + metronidazole or clindamycin may be used. The only agents for which oral administration is acceptable for PB are the quinolones.

Ultrasound probe configuration

Two different types of probes are available: end-fire and side-fire probe configurations and transmit frequencies of 6 to 10 MHz ( Figs. 1 and 2 ). End-fire probes execute the biopsy in a more anteroposterior plane and might therefore allow better access to the most lateral part of the peripheral zone. In addition, targeting the anterior horn of the prostate might be simplified. Evidence form retrospective studies suggests that an end-fire configuration results in greater detection of PCa. However, in a recent prospective randomized multicenter trial, no difference was seen in PCa detection rates when a systematic biopsy scheme was adopted. In another study, the side-fire probe was associated with a better patient tolerance profile, which may be related to the size of the tip and the fact that the insertion procedure for the side-fire probe seems to be gentler and better tolerated. With these considerations, the choice of probe remains operator dependent. The acoustic properties of soft tissue are similar to those of water, but clinically useful ultrasound energy does not propagate through air. For this reason, a water-density substance, termed a coupling medium, is used. The coupling medium, usually sonographic jelly or lubricant, is placed between the probe and the rectal surface. If the probe is covered with a protective condom, the coupling medium is placed between the probe and the condom, as well as between the condom and the rectal surface. TRUS should be performed in both transverse and sagittal planes.

( A ) Side-fire transrectal ultrasound probe. ( B ) Side-fire transrectal ultrasound probe with needle guide attached.

( A ) End-fire transrectal ultrasound probe with needle guide. ( B ) End-fire transrectal ultrasound probe with needle guide attached.

Anesthesia and patient positioning

Patients are usually placed in the left-lateral decubitus position, with the hips flexed up to 90°. A pillow placed between the knees helps maintain positioning. Make certain that the buttocks are flush with the end of the table to allow manipulation of the probe and biopsy gun without obstruction. Alternatively, some use the dorsal lithotomy position. A repeat DRE should be performed before insertion of the TRUS probe and abnormalities documented.

An important topic is pain control during and after biopsy. The overall sensitivity of the PB is probably only 70%. Many patients have to undergo a repeat biopsy, and this is an important part of AS protocols. If the patient experiences significant pain, it is difficult to convince them about the necessity of repeat biopsy. Periprostatic nerve block (PPNB) with 1% lidocaine is considered the standard anesthetic technique. The most common site of injection is bilaterally at the junction of the base of the prostate and seminal vesicles, because of the results of anatomic studies showing that the neuroatonomic pathway originates from the inferior hypogastric plexus located at the tip of seminal vesicles and passes between the prostate and rectum. Various infiltration sites have been studied ( Box 4 ), including the apex only, bilateral neurovascular bundles, apex and neurovascular regions, 3 locations (base, mid, and apex) posterolateral, and lateral to the tip of seminal vesicles. Ismail and colleagues reported that combined bilateral neurovascular bundles with apical infiltration resulted in more effective reduction in pain associated with TRUS biopsy than bilateral neurovascular infiltration alone, especially in younger patients. However, PPNB does not address somatic pain related to probe insertion and movement, which can be more painful than the biopsy, or pain caused by the infiltration itself. Cormio and colleagues recently reported their results on using 3 noninfiltrative anesthesia (NIA) protocols for TRUS biopsy. These investigators found that lidocaine-prilocaine cream was most effective in probe-related pain, whereas lidocaine-ketorolac gel was most effective in sampling-related pain. Some investigators have discussed the issue of whether PPNB should be associated with NIA or oral medications. Obek and colleagues have shown that the combination of PPNB with NIA was superior to PPNB alone. Pendleton and colleagues reported that oral administration of 75 mg tramadol/650 mg acetaminophen 3 hours before PNB seems to provide more effective pain control that PNB alone, without causing any additional side effects.

Grayscale examination

Grayscale TRUS is the classic technique for prostate imaging and enables a detailed visualization of the prostate ( Fig. 3 ). Prostate volume should be calculated and PSAD obtained in all patients undergoing TRUS. Volume is determined using the prolate ellipse formula (height × length × width × 1.83), which is intrinsic to most modern ultrasonography units. As a general reference, the average prostate volume in a 60-year-old to 70-year-old is approximately 48 mL.

Grayscale examination of prostate with classically described hypoechoic lesion at left base. Lesion was biopsy proven Gleason 8 (4 + 4) adenocarcinoma of the prostate.

The debate over targeting hypoechoic lesions in the prostate is still unsettled. A biopsy study of 3912 patients published in 2004 revealed that PCa was detected in 25.5% with a hypoechoic lesion and in 25.4% without such a lesion. Even more interesting is the per core distinction, which was 9.3% for hypoechoic and 10.4% for isoechoic areas. On the other hand, Toi and colleagues found that biopsies taken when a prostate lesion is identified by TRUS are almost twice as likely to show cancer than when no lesion is visible. The cancers were found to be of higher volume and grade. The investigators concluded that the search for and targeting hypoechoic lesion on TRUS remains important for PCa diagnosis.

Biopsy technique

The standard device used is a spring-driven 18-gauge needle core biopsy device or biopsy gun, which is passed through the needle guide attached to the ultrasound probe ( Fig. 4 ). The best visualization of the biopsy needle path is often in the sagittal plane. Grayscale images are superimposed with a ruled puncture path that corresponds to the needle guide of the TRUS unit. By design, the spring-loaded biopsy gun advances the needle 0.5 cm and samples the subsequent 1.5 cm of tissue, with the tip extending 0.5 cm beyond the area sampled. Place the tip of the needle approximately 0.5 cm posterior to the prostate capsule before activation. If the needle is advanced through the capsule before firing, this may result in sampling more anterior tissue. As a consequence, the most common site of cancer may be missed. Using the probe to compress the rectal mucosa before firing the needle may reduce rectal bleeding. The biopsy sample is placed in formalin solution provided by the reference laboratory. Sample submission can vary and is discussed later.

Example of a spring-loaded automatic 18-gauge PB needle.

Number and site of biopsy cores

A laterally directed systematic TRUS-guided PB with 12 cores is considered the standard procedure for PCa detection, resulting in a positive biopsy rate of 25% to 50%. Fig. 5 shows the recommended biopsy location and direction of a typical TRUS 12-core biopsy template.

Recommended systematic 12-core PB at base, mid, and apical prostate gland. Blue represents peripheral zone, the focus of the biopsy needle. Green represents the transition zone and tan represents the urethra.

Several studies have reported the higher yield of an EPB versus the old standard sextant biopsy, without an increase in the detection of insignificant cancer. The debate continues as to whether there is a value in adjusting the number of cores based on age or prostate volume. Sampling accuracy tends to decrease progressively with an increasing prostate volume. Ploussard and colleagues proposed that an extended biopsy scheme, with 21 cores obtained, increases cancer detection rates, especially if PSAD is less than 0.20 ng/mL.

On the other hand, it has been shown that the saturation technique as an initial PB strategy does not improve cancer detection. Jones has suggested that further efforts at extended biopsy strategies beyond 10 to 12 cores are not appropriate as initial biopsy strategy. In a systemic review, Eichler and colleagues showed that there is no significant benefit in taking more than 12 cores and methods requiring more than 18 cores have a poor side-effect profile. The AUA consensus has suggested that a 12-core biopsy is the recommended initial biopsy scheme; other investigators have advocated for additional biopsies, such as the 14-core biopsy by Mousa and colleagues.

In addition to the number of cores and prostate volume, the concept of biopsy core direction is equally important. The apex and the base of the peripheral gland are the most common cancer sites, which is where biopsies should be directed, whereas the parasagittal biopsies have been shown to have the lowest possibility of PCa at the initial biopsy. Based on landmark anatomic PCa location studies and furthered by knowledge of tumor location by Stamey, the addition of laterally directed biopsies has been shown to yield an approximately 5% to 35% increase in cancer detection rates. Most of the extradetected cancers were in anterior apical and far lateral midlobar regions, 2 areas well sampled by EPB. Contrary to earlier findings regarding the importance of parasagittally directed cores to detect transitional zone (TZ) cancer, it now seems established that because of their low prevalence at initial biopsy, cores of this area should be abandoned. Researchers form the University of Washington reported their experience with obtaining biopsies from the anterior apical region. These biopsies were directed under the capsule with the goal of sampling the peripheral zone anterior and distal to the TZ at apex. These investigators reported that the most common unique site of cancer was the anterior apex, where 17% of cancers would have been missed if not sampled. The use of EPB has resulted in more Gleason score concordance. San Francisco and colleagues reported an improvement on concordance rate from 63% to 72%. Milan and colleagues reported that rate of upgrading to worsening cancer was significantly reduced with EPB. With EPB, the risk of significant upgrading decreases because of higher sampling density and more accurate pathologic biopsy evaluation. The AUA has recently completed a white paper confirming that a 12-core systematic biopsy is optimal and that there was not compelling evidence that individual site-specific labeling of cores benefits clinical decision making regarding the initial management of PCa. The investigators recommend packaging no more than 2 cores in each jar to avoid reduction of cancer detection rates through inadequate tissue sampling.

Quality assurance

Benign or malignant conditions of the prostate are diagnosed by nuclear and architectural examination of prostate tissue. Therefore, 2 important factors are important in assessing the adequacy of a biopsy, namely, core length and the presence of glandular elements ( Box 5 ). Boccon-Gibod and colleagues suggested that the average needle biopsy length should serve as a measure of quality control, with 10 mm of tissue as the shortest acceptable length. Iczkowski and colleagues noted that the length of a single core sampled by sextant biopsy varied more than 3.6-fold. These investigators reported that a longer total tissue length increased the cancer detection rate, but this finding attained statistical significance only for cores obtained at apex. Obek and colleagues showed that a significant correlation with needle core length and cancer detection rates exists for all biopsy cores and is not limited to a specific prostate site. These investigators established a cutoff to predict a higher cancer detection rate and, thus, a potential core quality assessment tool. Obtaining cores longer than 11.9 mm was associated with 2.5 times higher likelihood of detection of PCa. Core length may vary according to different factors, including but not limited to the urologist who performs the biopsy, the needle, the biopsy retrieval and tissue handling methods, and the pathologic analysis. To investigate the adequacy of the samples obtained by PBs, Dogan and colleagues evaluated cores obtained form 378 patients. These investigators found that the highest incidence of absence of glandular elements was detected at apical and far lateral biopsy samples. Absence of glandular elements in 1, 2, and 5 biopsy samples were 50%, 27.8%, and 16.1%, respectively. The results have been found to be operator dependent. For patients with PSA between 4 and 10 ng/mL, cancer detection rates was lower in patients with absence of glandular elements. Collectively, these data suggest that clinicians must evaluate the pathology report in detail regarding core length and the presence of glandular elements. Pathologists must inform clinicians if they notice inadequacy of samples, and clinicians should even repeat the biopsy in necessary cases.

Repeat PB after initial negative biopsy

Studies of repeat PB after negative EPB indicate that up to 30% of patients have cancers that were not previously identified. Repeat PB seems to be justified in men with an initial negative biopsy but persistent suspicion of PCa based on age, comorbidities, DRE findings, repeated PSA measurements, other PSA derivatives (% free PSA, complexed PSA, PSAD, PSA velocity), or urinary PCA3 score. The use of the Progensa PCA3 assay (Hologic Gen-Probe, San Diego, CA, USA), which uses a PCA3 score with a cutoff value of 25 in post-DRE first-catch urine, has been approved by the US Food and Drug Administration to aid in the decision for repeat PB in men with 1 or more previous negative biopsies. The cutoff value remains debatable, because some studies have used 35 as the cutoff of abnormal. The superiority of PCA3 score compared with % free PSA was shown, indicating that a lower PCA3 score may prevent unnecessary repeat PB. PCA3 seems to have a role in reducing unnecessary PB at first repeat PB but not at second or more repeat PB sessions.

The number of biopsies needed in the repeat settings is still debatable. The NCCN guidelines suggest performing a second extended protocol and considering saturation biopsies only in patients with high risk of cancer after multiple negative biopsies. Several studies support the hypothesis that saturation biopsy (>20 cores) seems appropriate in the repeat biopsy setting. In a study from Italy, the best rebiopsy scheme varied according to the clinical characteristics of the patients. For patients with no atypical small acinar proliferation (ASAP), the ideal number of cores varied according to % free PSA. If % free PSA was less than 10%, the best scheme was a 14-core biopsy (including 4 TZ biopsies), whereas if % free PSA was greater than 10%, then the ideal scheme would include 20 core biopsy (including 4 TZ biopsies). In addition to the number of biopsies, location is an important issue in repeat biopsy. According to the European Association of Urology (EAU) 2013 guidelines, TZ biopsies should be considered in the repeat setting. In addition, the anterior apex seems to be the most common site of single-focus PCa, and repeat biopsies should include this distinct location. Djavan and colleagues reported in 2001 an original work on the risk of PCa on repeat biopsies performed 6 weeks after an initial negative set. These investigators found that cancer detection rates on biopsies 1, 2, 3, and 4 were 22%, 10%, 5%, and 4%, respectively, and that 58%, 60.9%, 86.3%, and 100% of patients who had RP had organ-confined disease on biopsies 1, 2, 3, and 4. The investigators concluded that biopsy 2 in all cases of a negative finding on biopsy 1 seems justified; however, further biopsies should be obtained only in select patients. Two important points need to be stressed: there was minimal delay between biopsies and these biopsies were all sextant. Thus, these findings may not apply in the modern extended biopsy era. Campos-Fernandes and colleagues in a more recent cohort with extended biopsies found that 18%, 17%, and 14% of patients had PCa in second, third, and fourth biopsies, respectively. Cancer detected at these sets of biopsies was significant in 85% of cases. Similarly, Tan and colleagues found significant PCa detected on third or greater PB, underscoring the importance of repeat biopsy in the setting of increased or increasing PSA despite negative previous PB. Pelvic magnetic resonance imaging (MRI) may be used to further investigate the possibility of an anterior located PCa in selected patients. Thus, no definitive recommendation can be made on when to stop biopsies when there is concern, and the decision should be individualized.

Another issue in the repeat biopsy setting is the role of transurethral resection of the prostate (TURP). Several investigators have reported the PCa detection rate offered by TURP. However, the 2013 EAU guidelines state “the use of diagnostic TURP instead of repeat biopsies is a poor tool for cancer detection.” The NCCN 2012 guidelines recommend TZ biopsies as part of repeat biopsy strategy, but they do not specifically comment on TURP. In a recent European study, in which patients were randomized to saturation biopsy only or saturation biopsy + TURP, TURP increased the detection of clinically significant cancer. The investigators comment that this strategy has to be balanced against the small increased incidence of urinary retention, emergency readmission, and longer hospital stay.

The role of transperineal biopsy in the repeat setting is debatable. The theoretic advantage of the transperineal route over the transrectal route stems from the direct longitudinal access to the prostate gland, potentially resulting in more efficacious sampling of the peripheral apical region, which seems to be underrepresented in the transrectal route. Several researchers have shown encouraging results with the use of template transperineal biopsies. However, this strategy has to be weighed against the need for anesthesia and increased morbidity with such an invasive procedure. Modern imaging studies such as MRI might have a relevant role in visualizing clinically significant cancers to facilitate precise sampling from any suspicious areas.