Prostate Biopsy

Indications[1]

1. Detection of prostate cancer in patients with:
   1. A raised PSA level (in the absence of urinary tract infection, acute urinary retention or acute prostatitis)
   2. Abnormal digital rectal examination of the prostate
2. Restaging and reassessment in patients for:
   1. Rising PSA following non-surgical treatment such as radiotherapy, brachytherapy, cryotherapy or HIFU
   2. Active surveillance protocols in patients with known low grade cancer
   3. Histology suspicious but not diagnostic for carcinoma
3. As part of a protocol in an approved clinical trial

Contraindications

1. Significant coagulopathy
2. Severe immunosuppression
3. Acute prostatitis

Approach: Transrectal vs. transperineal

Transrectal biopsy

• Trajectory of needle is through rectum and into prostate

Insert image (wiki)

Transperineal biopsy

• Trajectory of needle is through skin (avoids rectum) and into prostate
• Advantages (3):
  1. Reduced infectious and other complication rates
  2. Improved identification of apical tumors
  3. Can be done in patients without a rectum (e.g., surgical extirpation, congenital anomaly)
• Disadvantages (1):
  1. May need for more anesthesia, but can be done under local anesthetic

Insert image (wiki)

Preparing for biopsy

Anti-coagulation

• Low-dose aspirin does not need to be discontinued[2]
• Warfarin and clopidogrel should be stopped 7-10 days before prostate biopsy
• Novel oral anticoagulants apixaban, dabigatran, and rivaroxaban are stopped 2-5 days before
  • Rivaroxaban may increase stroke risk if stopped; therefore bridging with some other anticoagulant such as heparin is recommended.
• For patients with underlying coagulopathy or on warfarin, prostatic biopsy should not be performed until the INR has been corrected < 1.5 if the patient has low risk for a thromboembolic event. Because of the higher risk for thromboembolic events (e.g., mechanical valves) on warfarin, bridging anticoagulation with unfractionated heparin or low-molecular weight heparin is suggested.

Antibiotic prophylaxis

Transrectal

• Recommended for all patients undergoing prostate biopsy
• Regimen:
  • 2019 AUA Antibiotic Prophylaxis Guidelines: fluoroquinolone OR 1st/2nd/3rd gen. cephalosporin (ceftriaxone commonly used) + aminoglycoside
  • 2015 CUA Antibiotics Prophylaxis Guidelines: no specific regimen
  • Campbell’s: For patients at risk for developing endocarditis or infection of prosthetic joints, pacemakers, and automated implanted cardiac defibrillators, prophylaxis should consist of intravenous ampicillin (vancomycin, if penicillin allergic) and gentamicin preoperatively, followed by 2 to 3 days of an oral fluoroquinolone.
  • Presence of fluoroquinolone resistant organisms on a rectal swab culture may not always be associated with clinical infection.
    • A multi-institutional cohort study of 136 men undergoing rectal swab cultures immediately before biopsy found fluoroquinolone resistant E. coli in 22% of cultures. Patients received ciprofloxacin +/- gentamycin for prophylaxis. Post-biopsy fever occurred in 5 patients, and only 1 of them had a positive rectal screen for resistant E. coli.[3]
  • The use of targeted prophylaxis after rectal flora swabbing and culture has been shown to have some utility compared with empirical antibiotic prophylaxis in some series
• 2011 Cochrane review evaluating antibiotic prophylaxis for TRUS biopsy of the prostate[4]
  • 19 studies including 3,599 patients.
  • Comparing antibiotics vs. placebo/no antibiotics (9 trials): antibiotics significantly reduce risk of (5):
    1. Bacteriuria (risk ratio (RR) 0.25)
    2. UTI (RR 0.37)
    3. Bacteremia (RR 0.67)
    4. Fever (RR 0.39)
    5. Hospitalization (RR 0.13)
       • Most data derived from studies with quinolones
  • Comparing antibiotics +/- enema, only the risk of bacteremia (RR 0.25, 95% CI 0.08-0.75) was diminished in the antibiotic + enema group
  • Comparing short-course (1 day) versus long-course (3 days) antibiotics (7 trials): long course significantly better than short-course treatment only for bacteriuria (RR 2.09)
  • Comparing single versus multiple dose: significantly greater risk of bacteriuria for single-dose treatment (RR 1.98)
  • Comparing oral versus systemic administration - intramuscular injection (IM), or intravenous (IV) - of antibiotics, no significant differences in the groups for bacteriuria, fever, UTI and hospitalization.
  • Zani, Emerson L., Otavio Augusto Camara Clark, and Nelson Rodrigues Netto Jr. "Antibiotic prophylaxis for transrectal prostate biopsy." Cochrane Database of Systematic Reviews 5 (2011).

Transperineal

• Risk of infection is decreased compared to transrectal since trajectory avoids rectum
• NORAPP Trial (2022)[5]
  • Population: 555 patients referred for prostate biopsies
    • Excluded patients at high-risk (clinical suspicion of urinary tract infection together with a positive urine dipstick for leukocytes and nitrate, recurring or recent urinary tract infection (<1 month), indwelling urinary catheter, immunodeficiencies, high risk of infective endocarditis, or history of thromboembolic disease) of post-biopsy infection
    • All patients with a positive MRI underwent two to four biopsies per target. Systematic biopsies were done as an addition to target biopsies in biopsy naive patients and in all patients with a negative MRI.
  • Randomized (open-label) to antibiotics (cefuroxime 1.5g IV or IM 30 minutes before biopsy) vs. no antibiotics
  • Outcomes:
    • Primary: difference in the rate of urosepsis or urinary tract infections requiring hospitalisation up to 2 months after biopsy
    • Secondary: difference in the rate of urinary tract infections not requiring hospitalisation by 2 months
  • Results:
    • Primary outcome: no significant different in rate of urosepsis or UTI requiring hospitalisation up to 2 months after biopsy (0% antibiotics vs. 0% no antibiotics)
    • Secondary outcome: no significant difference in rate of UTI not requiring hospitalisation by 2 months (0.4% antibiotics vs. 1.1% no antibiotics)
      • NNT with antibiotic prophylaxis to avoid one UTI not requiring hospitalisation: 137
  • Interpretation: In patients undergoing transperineal biopsy, antibiotics do not significantly reduce the risk of infections
  • Jacewicz, Maciej, et al. "Antibiotic prophylaxis versus no antibiotic prophylaxis in transperineal prostate biopsies (NORAPP): a randomised, open-label, non-inferiority trial." The Lancet Infectious Diseases (2022).

Cleansing Enema

• Advantages
  • Decreases the amount of feces in the rectum, thereby producing a superior acoustic window for prostate imaging
  • Effect on reducing infections is debatable
• Disadvantage
  • Requires coordinating timing of biopsy to effect of cleansing enema
• 2015 CUA Antibiotics Prophylaxis Guidelines: insufficient evidence to recommend routine use of enemas

Number and location of cores

• Approach
  • Transrectal
    • The extended 12-core systematic biopsy that incorporates apical and far-lateral cores is the current recommended method.
      • Previously, the standard number of cores was 6. However, it has been shown that increasing the number of cores from 6 to 12 significantly increases cancer detection rate.
        • Increasing the number of cores to 18 or 21 (often termed saturation biopsy) as an initial biopsy strategy does not appear to result in a similar increase from 6 to 12. Saturation biopsy is more likely to be considered in the setting of a prior negative biopsy, though in the era of MRI this may not be relevant.
  • Transperineal
    • 20 cores (2 cores (different locations) taken from 5 sites on each side)[6]
      • 5 sites
        1. Posterior medial
        2. Anterior medial
        3. Posterior lateral
        4. Anterior lateral
        5. Base
    • 3-4 cores from target
• The transitional zone and seminal vesicles are not routinely sampled because these regions have been shown to have consistently low yields for cancer detection at initial biopsy
  • Isolated transition zone tumors without peripheral zone involvement occur < 5% of the time.
  • Transitional zone and anteriorly directed biopsies may occasionally prove necessary to diagnose prostate cancer in those patients with persistently elevated PSA levels and prior negative biopsies. More recently, MRI is often used to detect and guide biopsies of these anterior tumors that may escape standard TRUS prostate biopsy
  • The seminal vesicles are not routinely performed unless there is a palpable abnormality, with some authors recommending seminal vesicle biopsy when the PSA is > 30 or if brachytherapy is being considered
• When biopsy specimens are taken from different sextant areas of the prostate, they should be submitted to pathology in separate containers
  • An AUA white paper recently outlined the recommended processing of prostate biopsy samples, and the review did not provide compelling evidence that individual site–specific labeling of cores benefits clinical decision making regarding the management of prostate cancer (Bjurlin et al, 2013). [still relevant?]

Technique

Equipment

• Ultrasound machine and biplanar probe
  • Probe may be configured as side-fire vs. end-fire
    • Randomized trials found no significant difference in prostate cancer detection rates between these two approaches[7]
  • The best visualization of the biopsy/needle path is in the sagittal plane
• Disposable sheaths to cover the TRUS probes (e.g. condom)
• Biopsy gun
  • The 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. Therefore, when sampling the PZ, the needle tip may be placed 0.5 cm posterior to the prostate capsule before firing; advancing the needle to or through the capsule can result in sampling of more anterior tissue, missing the most common location of cancers.[8]
• Local anesthetic
• Long 22-guage spinal needle
• 10cc syringe
• Ultrasound-specific lubricating gel
• Lubricating jelly
• Specimen containers
• Prepare equipment
  • Apply ultrasound-specific lubricating gel inside disposable sheath to cover the TRUS probe
  • Insert probe into disposable sheath
  • Apply constriction method so that lubrication jelly stays at tip of probe
  • Prepare biopsy gun

Anesthesia

• Approaches[9]
  • Periprostatic nerve block
    • Nerves can be blocked with either unilateral or bilateral injection, around the apex or base of the gland (in the groove between the gland and seminal vesicles).
    • Typically performed using a long 22-gauge spinal needle, and the biopsy channel of the ultrasound probe
    • Method 1[10]
      • In the groove between the seminal vesicle and the base of the prostate gland, near the bladder base (near the nerve bundles)
        • Can be easily identified as a hypoechoic (dark) area on TRUS
        • See Figure
      • The injection is performed twice, once either side the midline.
    • Method 2 (transrectal)[11]
      • A position just lateral to the midline, and away form the external sphincter is chosen. The needle is passed through rectal mucosa and local anaesthetic instilled, so that the anaesthetic pools within fascial layers (presumed to the Denonvillers' fascia) and bathes the posterior surface of the gland, from the apex up to the base.
      • The injection is performed twice, once either side of the midline.
    • Agent
      • 1% lidocaine without epinephrine
        • 5 ml per side, is sufficient to provide pain relief[12]
      • 1% lidocaine without epinephrine mixed with 8.4% sodium bicarbonate[13]
        • Can use up to 20-30cc
    • Conflicting evidence of if direct infiltration into the prostate (intraprostatic injection) can augment the anesthetic benefit seen with periprostatic injection
  • Topical rectal anaesthetic gel
  • Variations in probe design
  • Glyceryl trinitrate (GTN) paste
  • Oral NSAIDs
  • Inhaled nitrous oxide
  • Intravenous analgesia

Transrectal

• Position: usually left lateral decubitus position with knees and hips flexed 90°; can also be done lithotomy
  • Lithotomy is preferred for brachytherapy treatment planning or placement of fiducial gold markers for external-beam therapy

• Perform a DRE to (2):
  1. Rule out any rectal pathology that would contraindicate insertion of the probe
  2. Allow identification of any palpable prostatic abnormalities to which special attention could be paid during ultrasound examination
• Insert the lubricated ultrasound probe slowly and with pressure to dilate the anal sphincter.
• Adjust the gain to provide a uniform mid-gray image of the normal peripheral zone
  • The shading of the peripheral zone should be the homogenous gray standard by which other areas of the prostate are classified as hyperechoic, hypoechoic, or isoechoic.
• Scan the prostate, from the base to the apex
  • Evaluate for any hypoechoic lesions in the prostate
  • Scan in the axial/transverse plane, followed by the sagittal plane
    • Rotate probe counter-clockwise to access right lobe of prostate, and clockwise to access left lobe of prostate
• Measure the prostate size.
  • Measuring the prostate size is recommended prior to infiltration of local anaesthesia[14]
  • The prostate is measured in 3 planes. Typically, in the axial/transverse view, height and width are measured and in the sagittal/lateral view, length is measured
• Perform periprostatic nerve block
• Warn patients that they should expect a loud click when the biopsy gun is fired.
• Take biopsies following appropriate template
  • 12-core
    • Lateral apex, mid, base
    • Medial apex, mid, base
    • The initial biopsy is taken midway between the mid-point of the prostate gland and the lateral margin
    • The probe is then rotated laterally and a subsequent biopsy is taken at the same level but more laterally placed to sample tissue from the anterior horn of the peripheral zone (PZ).
  • Use needle guide button on ultrasound machine, if available
  • It is important to place the biopsy needle correctly at the prostate capsule in order to sample the outer-most part of the PZ.
    • The biopsy needle travels a few millimetres forward of its position on TRUS and a frequent error is the insertion of the biopsy needle into the PZ prostatic tissue which results in the biopsy needle passing further into then gland and not sampling the area close to the capsule which is frequently the site of the PZ cancers.
  • It is important to ensure the biopsy sampling is spatially distributed correctly at the base, mid-gland and apex.
  • Care must be taken not to rebiopsy the same area particularly in smaller prostates as this can give misleading information about the extent of the cancer within the gland.
• Remove ultrasound probe and apply digital pressure to biopsied area to reduce bleeding
• Inform patient of reasons to return to hospital

Transperineal

• See video
• Position: usually lithotomy
• Perform a DRE to (2):
  1. Rule out any rectal pathology that would contraindicate insertion of the probe
  2. Allow identification of any palpable prostatic abnormalities to which special attention could be paid during ultrasound examination
• Insert the lubricated ultrasound probe slowly and with pressure to dilate the anal sphincter.
• Scan the prostate, from the base to the apex
  • Evaluate for any hypoechoic lesions
  • Rotate probe counter-clockwise to access right lobe of prostate, and clockwise to access left lobe of prostate
• Measure the prostate size.
  • Measuring the prostate size is recommended prior to infiltration of local anaesthesia[15]
  • The prostate is measured in 3 planes. Typically, in the axial/transverse view, height and width are measured and in the sagittal/lateral view, length is measured
• Perform periprostatic nerve block
  • Local anesthetic injection: 1% Lidocaine without epinephrine mixed with 8.4% sodium bicarbonate injected bilaterally into the perineal skin and peri-prostatic space to a depth of 10 mm as well as into the pelvic floor musculature, for a total of 20-30 cc[16]
• Warn patients that they should expect a loud click when the biopsy gun is fired.
• Take biopsies following appropriate template
• Remove ultrasound probe and apply digital pressure to biopsied area to reduce bleeding
• Inform patient of reasons to return to hospital

Complications[17]

1. Bleeding
   1. Hematuria (≈50%)
      • Needs intervention (e.g. clot retention) in <1%
   2. Hematospermia (≈50%)
      • Can persist >4 week after biopsy in ≈30%
   3. Rectal bleeding (≈30%)
      • Needs intervention in ≈2.5%
      • Avoided with transperineal biopsy
2. Infection (prostatitis, fever, epididymitis)
   • Transrectal (≈5-7%) higher than transperineal
   • Transrectal
     • Infection requiring hospitalization: ≈1-3%
       • Rates of hospital admission and mortality after TRUS-biopsy[18]
         • Population: Population-based cohort study of 75,190 men who underwent a transrectal ultrasound guided biopsy in Ontario, Canada, between 1996 and 2005
         • Results:
           • The 30-day hospital admission rate increased significantly from 1% in 1996 to 4% in 2005, the majority (72%) of which were for infection related reasons.
           • The overall 30-day mortality rate was 0.09% but did not change during the study period.
         • Conclusions: Hospital admission rates for complications following TRUS guided prostate biopsy have increased dramatically during the last 10 years primarily due to an increasing rate of infection related complications.
       • Risk factors for prostate biopsy-related infection (6):
         1. Non-White race
         2. Increased number of comorbidities
         3. Diabetes mellitus
         4. Prostate enlargement
         5. Foreign travel
         6. Recent antibiotic use
3. Transient (≈1 month) lower urinary tract symptoms 6-25%
4. Urinary retention <1%
5. Transient (≈1 month) erectile dysfunction <1%
6. False-negative (variable rate based on PSA)
   • Initial cancer detection rate for patients with a PSA between 4 and 10 μg/mL is 22%; subsequent biopsies for an elevated PSA result in a cancer detection rate of 10% on the second biopsy, 5% on the third, and 4% on the forth
   • Data from the large European screening study suggested that as the number of biopsy sessions increased to ultimately diagnose prostate cancer, the cancers diagnosed after several biopsy sessions were generally of lower grade and stage

Advanced and investigational techniques for prostate biopsy

• Newer imaging modalities allowing for the potential of targeted biopsy include Doppler to determine vessel density, determination of the elasticity of an area, endorectal MRI with dynamic contrast enhancement and diffusion weighting, and MRI spectroscopy
• TRUS/MRI fusion via a software platform
  • Combines the familiarity of realtime TRUS guidance with detailed information from a diagnostic multiparametric MRI and superimposes both images via software image reconstruction
• Cognitive fusion biopsy
  • Requires no additional equipment and relies on an experienced operator reviewing a suspicious lesion on MRI and then directing the biopsy needle in the direction of suspicious lesions during the standard TRUS biopsy procedure.
  • A primary disadvantage of this technique is the inability to record and confirm biopsy needle placement as well as interuser variability. In expert hands, this has been shown to be as good as software fusion

Questions

1. List complications of a TRUS biopsy
2. What are some advantages/disadvantages of transperineal biopsy?

Answers

1. List complications of a TRUS biopsy
   1. Hematuria
   2. Hematospermia
   3. Rectal bleeding
   4. Infection
   5. Urinary retention
   6. False-negative
2. What are some advantages/disadvantages of transperineal biopsy?
   • Advantages:
     1. Reduced infectious and other complication rates
     2. Improved identification of apical tumors
   • Disadvantages:
     1. May need more anesthesia

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 109
• Lightner, Deborah J., et al. "Best practice statement on urologic procedures and antimicrobial prophylaxis." The Journal of Urology 203.2 (2020): 351-356.
• Harvey, C. J., et al. "Applications of transrectal ultrasound in prostate cancer." The British journal of radiology 85.special_issue_1 (2012): S3-S17.