Prostate Biopsy

Grayscale Trans-Rectal Ultrasound (TRUS)

• Probe frequency
  • Increasing the frequency increases the resolution and decreases the depth of penetration
  • Decreasing the frequency increases the depth of penetration and decreases the resolution
  • The commonly used 7-MHz transducer produces a high-resolution image with a focal range from 1-4 cm from the transducer (best for peripheral zone where most cancers arise)
  • Lower frequency transducers (e.g., older 4-MHz transducers) have a focal range from 2-8 cm but at lower resolution
• General urological uses of a TRUS (5):
  1. Assess prostate volume
  2. Locate focal prostate abnormalities
  3. Assess for obstructive cause of infertility (dilated seminal vesicles secondary to ejaculatory duct obstruction)
  4. Guide prostate biopsies
  5. Guide placement of brachytherapy seeds

TRUS Anatomy of the Prostate

• Traditionally described based on a pathologic zonal architecture:
  • Anterior fibromuscular stroma (FS), which is devoid of glandular tissue
  • Transition zone (TZ)
  • Central zone (CZ)
  • Periurethral zone
  • Peripheral zone (PZ)
  • CZ and PZ cannot be distinguished from each other on US, and are often collectively referred to as the PZ on TRUS
  • The TZ is generally hyperechoic compared to the CZ and PZ
  • Click here for image
  • See video on GU Sonography of the Urinary Bladder, Scrotum & Prostate
• Calcifications along the surgical capsule, known as the corpora amylacea, highlight the plane between the PZ and TZ (multiple diffuse calcifications are a normal, often incidental finding and represents a result of age rather than a pathologic entity)

Estimating Prostate Volume

• Most formulas assume that the gland conforms to an ideal geometric shape: either an ellipse (π/6 × transverse diameter × AP diameter × longitudinal diameter), sphere (π/6 × transverse diameter3), or a prolate (eggshaped) spheroid (π/6 × transverse diameter2 × AP diameter).
  • All formulas reliably estimate gland volume and weight, with correlation coefficients > 0.90 with radical prostatectomy specimen weights, because 1 cm3 = approximately 1 g of prostate tissue.
  • Planimetry is the most accurate means of volume measurement by US
    • Planimetry allows for variation in shape as the area is calculated in consecutive ultrasonographic cross-sections. The area is multiplied with the distance between the cross-sections and the total volume is determined by summation of all contributions.§

Prostate lesions on TRUS

• The peripheral zone is used as the reference for isoechoic when describing lesions
• Most (60%) prostate cancers are hypoechoic; however, can also be iso (39%) or even hyperechoic (1%)§
  • Images of hypoechoic lesions on TRUS
• A hypoechoic lesion contains cancer ≈20% of the time.
  • While there is a need to biopsy hypoechoic lesions, these lesions are not pathognomonic for cancer and do not correlate with the aggressiveness of the disease as measured by Gleason score.
  • Differential diagnosis of hypoechoic lesions on TRUS (5):
    1. Granulomatous prostatitis
    2. Prostatic infarct
    3. Lymphoma
    4. BPH nodules
    5. Normal urethra
• Many cancers, including hematologic malignancies of the prostate, are isoechoic
  • Prostatic cysts
    • May be congenital or acquired but are rarely clinically significant, regardless of cause
    • Congenital prostatic cystic lesions may arise from either müllerian (prostatic utricles and müllerian duct cysts) or wolffian (ejaculatory duct and SV cysts) structures
      • Enlarged prostatic utricle
        • A diverticular projection from the posterior urethra at the level of the verumontanum
        • Appears as a midline anechoic structure
        • Associated with genital anomalies, including hypospadias (most common), ambiguous genitalia, undescended testes, and congenital urethral polyps
      • Müllerian duct cysts
        • Result from failure of the müllerian ducts to fuse with the urethra.
        • Appears as a midline anechoic structure; generally ovoid to pear shaped, with the cyst neck oriented toward the verumontanum.
        • Should prompt renal US to assess for unilateral renal agenesis
      • SV cysts
        • Can be caused by congenital or acquired obstruction of the ejaculatory duct
        • Associated with cystic renal disease
        • Should prompt renal US to assess for unilateral renal agenesis
        • Zinner syndrome (3):
          1. Ipsilateral SV cyst
          2. Ejaculatory duct obstruction
          3. Unilateral renal agenesis
• TRUS appearance after treatment
  • External-beam radiation monotherapy therapy usually results in decreased volume by 6 months after treatment.
  • With brachytherapy, prostate volume declines significantly after treatment, with a 37% size reduction at 1 year after treatment and > 50% reduction 8 years after implantation
  • Irradiated prostates are diffusely hypoechoic
  • Androgen ablation with luteinizing hormone–releasing hormone analogues will cause ≈30% volume decrease with androgen deprivation in prostates with and without cancer
  • Volume decreases by ≈21% at 6 months with 5-ARIs

Technique

Contraindications (3):

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

Preparing for biopsy

Anti-coagulation

• Low-dose aspirin does not need to be discontinued
• Anticoagulant therapy
  • Warfarin, clopidogrel, etc. 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

• 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.
  • The presence of fluoroquinolone resistant organisms on a rectal swab culture has not always translated into clinical infection. In one multi-institutional study, rectal swab cultures immediately before biopsy in 136 men who received ciprofloxacin and gentamicin for prophylaxis had fluoroquinolone resistant E. coli in 22% of cultures (Liss et al, 2011). Only 5 (4%) patients had post-biopsy fever, and only 1 of them had a positive rectal screen for resistant E. coli.
  • 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
  • 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).

Cleansing Enema

• Decreases the amount of feces in the rectum, thereby producing a superior acoustic window for prostate imaging; effect on reducing infections is debatable
• Many clinicians may elect not to use an enema because this may allow more spontaneous performance of a prostate biopsy
• 2015 CUA Antibiotics Prophylaxis Guidelines: insufficient evidence to recommend routine use of enemas

Analgesia

• Proper analgesia is performed by TRUS-guided periprostatic infiltration of local anesthetic injection (5 mL lidocaine) bilaterally at the level of the seminal vesicles near the bladder base (near the nerve bundles)
  • Direct infiltration into the prostate (intraprostatic injection) can augment the anesthetic benefit seen with periprostatic injection
• Typically performed using lidocaine, a long 22-gauge spinal needle, and the biopsy channel of the ultrasound probe

Position

• Patients are usually placed in the left lateral decubitus position with knees and hips flexed 90°.
• The lithotomy position is used by some and is preferred for transperineal biopsies, brachytherapy treatment planning, or placement of fiducial gold markers for external-beam therapy
• The best visualization of the biopsy path is in the sagittal plane
• INSERT FIGURE

Number and location of cores

• 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.
  • 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?]

Complications[1]

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%
2. Infection (prostatitis, fever, epididymitis) ≈5-7%
   • Needs hospitalization in ≈1-3%
     • Rates of hospital admission and mortality after TRUS-biopsy[2]
       • 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

Transperineal biopsy

• Advantages:
  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. May need for more anesthesia, but can be done under local anesthetic

Insert figure

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 uses of a TRUS
2. What is the differential diagnosis of a hypoechoic lesion on TRUS?
3. List complications of a TRUS biopsy
4. What are some advantages/disadvantages of transperineal biopsy?

Answers

1. List uses of a TRUS
   1. Estimate prostate volume
   2. Locate focal prostate abnormalities
   3. Assess for obstructive cause of infertility
   4. Guide prostate biopsies
   5. Guide placement of brachytherapy seeds
2. What is the differential diagnosis of a hypoechoic lesion on TRUS?
   1. Granulomatous prostatitis
   2. Prostatic infarct
   3. Lymphoma
   4. BPH nodules
   5. Normal urethra
3. List complications of a TRUS biopsy
   1. Hematuria
   2. Hematospermia
   3. Rectal bleeding
   4. Infection
   5. Urinary retention
   6. False-negative
4. What are some advantages/disadvantages of transperineal biopsy?

• Advantages:
  1. Reduced infectious and other complication rates
  2. Improved identification of apical tumors
• Disadvantages:
  1. Needs more extensive anesthesia

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 109