Michael J. Amirian, MD
Leonard G. Gomella, MD, FACS
BASICS
DESCRIPTION
• Transrectal ultrasound-guided (TRUS) prostate biopsy (PB) is the gold standard for diagnosis of prostate cancer (CaP)
• While CaP screening is controversial, a subset of men have a negative TRUS PB with persistent or increasing elevation in PSA. This can be a challenge for urologist and the patient
• Repeat PB performed after negative PB suggests up to 30% of patients have cancers not previously identified (1)
EPIDEMIOLOGY
Incidence
800,000–1.2 million prostate biopsies are performed in the United States annually
Prevalence
• 24.1% of men in a screening population undergoing TRUS diagnosed with PCa
• False-negative rate for TRUS PB as high as 35%
– Cancer detection rate as high as 14% after 3rd repeat biopsy
RISK FACTORS
• Both technical and anatomical considerations contribute to a false-negative PB
• Advances in biopsy techniques have improved positive sampling rates
– Digital-direct biopsy without ultrasound guidance provides inadequate sampling
– TRUS guided is gold standard
<10 cores are considered inadequate for cancer detection
“Double sextant” or 12-core with inclusion of laterally directed cores have lower false-negative rates
• Anatomical
– Large gland size (>50 cc) may limit detection of CaP on standard core biopsy
– End-fire ultrasound probe allows better sampling anterior and apical prostate gland
These areas likely to harbor unrecognized malignancy in larger glands
• High-grade cancers (Gleason 9–10) may not have PSA elevation
Genetics
• CaP has both familial and genetic component
– Relative risk increases with number of 1st-degree relatives affected
Higher index of suspicion if 1st-degree relatives have diagnosis of prostate malignancy
PATHOPHYSIOLOGY
• 12 biopsy cores from a standard 18G needle enables only 0.04% of prostate gland to be evaluated for pathology (2)
• PSA elevations can be from non-PCa causes
• Series reporting follow-up biopsy results (Mo)
– In 2012 Ca detection rates on follow-up biopsies 1, 2, 3, and 4 were 22%, 10%, 5%, and 4%, respectively; 58%, 60.9%, 86.3%, and 100% of patients who had RP had organ-confined disease on biopsies 1, 2, 3, and 4.
– A 2008 series with extended biopsies found CaP 18%, 7%, and 14% of patients had PCa in 2nd, 3rd, and 4th biopsies, respectively; significant CaP in 85% of cases (3).
ASSOCIATED CONDITIONS
The following can cause elevated PSA: infection, recent instrumentation, benign prostatic hypertrophy (BPH)
GENERAL PREVENTION
• Obtain serial PSA at same lab; avoid sexual activity for 24 hr before
• Preventing a false-negative PB is greatly dependent on technique
– 12-core template is now standard
6 parasagittal plus 6 lateral cores
– Sextant (6-core) biopsy can miss up to 50% of small tumors
– No evidence of increased complication rate of 12-core compared to sextant biopsy
DIAGNOSIS
HISTORY
• Prior history of negative prostate biopsies
• Evaluate for nonmalignant causes of elevated PSA
– Prostatitis
– Recent instrumentation of genitourinary tract
– Rarely sexual activity, bicycling can briefly elevate
• Increase risk of PCa
– 1st-degree relative with PCa and recent data suggestion increased risk with a relative with breast cancer
Increase risk by 120–150%
– Ethnicity: Black race highest risk
– History of exposure to exogenous androgen or anabolic steroid use
• Percent-free PSA
– With negative prior biopsy and low percent-free PSA (<12%) have higher risk of malignancy
• PSA velocity
– Rate of change of PSA over 1-yr period
– Recommend biopsy if PSA velocity exceeds 0.35 ng/mL/yr
– PSA velocity independent predictor of overall PCa, intermediate- and high-grade cancer.
PHYSICAL EXAM
• Digital rectal exam (DRE)
– Induration or nodularity
Concerning for malignancy
– Symmetric and enlarged gland
BPH more likely with elevated PSA and negative biopsy
– Tenderness or bogginess on exam
Likely acute prostatitis
• Decreased testicular volume
– Consider exogenous androgen exposure
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Free/total PSA (4)
• Prostate cancer antigen 3 (PCA3)
– Gene that is overexpressed in PCa; measured in 1st voided urine after attentive digital rectal exam
– FDA approved for men >50 yr who have had 1 or more previous negative biopsies
– Cutoff debatable 25–35
– Compared to PSA
Lower sensitivity (67%); higher specificity (83%)
Some studies suggest superior to F/T PSA
Patient stratified into lower risk or higher risk of having a positive biopsy
Imaging
• MRI may identify anterior tumor not reached by biopsy needle
– T2-weighted MRI
Identify focal lesions within gland
Need to wait 6–8 wk after negative biopsy as recent biopsy sites cause distortion
– Multiparametric (mp) MRI
Combination of dynamic contrast-enhanced MRI, MR spectroscopic imaging, and diffusion-weighted imaging; need access to experienced center
– Contrast-enhanced TRUS
Neovascularity of tumor enhances with microbubble contrast agent (not FDA approved)
Targeted biopsy show increase sensitivity from 38–65% vs. unenhanced imaging
– Color Doppler of limited utility w/o contrast
– Elastography ultrasound: Tumors allow less displacement with compression than normal tissue; color coded map allows targeted biopsy; not widely available
• MRI TRUS fusion biopsy may help identify specific lesions for directed biopsy
Diagnostic Procedures/Surgery
• Mapping/saturation biopsy
– Obtaining 20 or more cores with standard biopsy technique; can be transrectal but more likely to be done transperineally using a brachytherapy-like template guide
– Studies vary in yield of detection with increased cores; increased morbidity
– Usually require additional anesthesia
• Transitional zone targeted biopsy
– 15% increased detection in gland >50 cc
• Template transperineal PB
– May allow better sampling of peripheral zone
– Controversial if better cancer detection
• MRI and ultrasound fusion targeted biopsy
– Stored MRI is fused with real-time ultrasound using a digital overlay
– Series report 41% vs. 18% compared to conventional ultrasound in detection of CaP in men with prior negative biopsies
– Requires specialized training and equipment
Pathologic Findings
• Quality assurance in the initial biopsy is critical. Data suggests a core length of >10 mm and the presence of glandular elements suggest an adequate sample
• High-grade prostatic intraepithelial neoplasia (HGPIN) 0–24.6% on initial biopsy (median 4%)
– Considered by some to be premalignant lesion: 23–35% risk of diagnosis cancer on subsequent biopsy; however, EAU does not recommend repeat biopsy with HGPIN
• Atypical small acinar proliferation (ASAP)
– Incidence 0.7–23.4%, median 4.4%
– Increased CaP risk on subsequent biopsy (up to 40%)
DIFFERENTIAL DIAGNOSIS
• ASAP
• BPH
• HGPIN
• Prostatitis
TREATMENT
GENERAL MEASURES
• Most recommendations are for repeat biopsy for patients with either ASAP or multifocal HGPIN within 3–6 mo regardless of PSA (5)
• For others with negative biopsy and persistently elevated or rising PSA, consider the use of supplementary lab tests such as PCA3, free/total PSA Confirm MDx to guide decision
• Repeat PB appears justified in:
– An initial negative biopsy and persistent suspicion of PCa based on age, comorbidities, DRE findings, repeated PSA, PSA derivatives, (% free PSA, complexed PSA, PSAD, PSA velocity, or urinary PCA3 score) and patient and physician preferences
• With concerns over the interpretation of the earlier biopsy, consider a 2nd opinion
MEDICATION
First Line
• Limited utility in managing elevated PSA
• Antibiotics if presumed prostatitis cause of elevation
– 2–3-wk course of oral antibiotics
– Sulfamethoxazole and trimethoprim (Bactrim DS) BID or ciprofloxacin 500 mg BID
Repeat PSA after termination of treatment
– Studies have not shown routine antibiotics decreased need for future biopsy
• 5-α reductase inhibitors
– Finasteride 5 mg or dutasteride 0.5 mg PO QD for 6 mo
Should lower PSA by 50% after 6 mo but not proven useful in determining repeat biopsy, but any PSA rise after 6 mo raises CaP risk
Second Line
N/A
SURGERY/OTHER PROCEDURES
• The number of cores on repeat biopsy is debatable. NCCN guidelines suggest performing a 2nd extended biopsy and consider saturation biopsies only in with high risk of cancer after multiple negative biopsies
• Transurethral resection prostate biopsy
– Once advocated for diagnosis of transition zone cancers
– Less than 5% CaP are transitional zone CaP without concomitant peripheral zone tumors
– Improved TRUS technique in sampling transitional zone; no definite value in performing transurethral resection PB
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• The European Randomized Study of Screening for PCa (ERSPC)-based model has several calculators to determine outcome after negative biopsy (http://www.prostatecancer-riskcalculator.com/)
• Genomic testing may help determine risk after negative biopsy
– Confirm MDxTM: Epigenetic assay to distinguish men who have a true-negative biopsy from those with occult cancer
– Identifies methylation signature in area near PCa location using recent prostate biopsy material
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• There is no PSA threshold that can rule out PCa in any age range
– Regardless of initial PSA value, a PSA velocity greater than 0.75 ng/mL/yr warrants repeat biopsy
• Lowering PSA threshold for initial biopsy
– Many urologists recommend PB to men younger than 60 yr of age once PSA >2.5 ng/mL; enables earlier CaP detection
COMPLICATIONS
See Section I: “Prostate biopsy, Infections and Complications”
FOLLOW-UP
Patient Monitoring
If low risk with negative biopsy can be followed with routine surveillance protocol
Patient Resources
National Cancer Institute Fact Sheet: Prostate-Specific Antigen (PSA) test. www.cancer.gov/cancertopics/factsheet/detection/PSA
REFERENCES
1. Zaytoun O, Moussa AS, Gao T, et al. Office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in repeat biopsy population. J Urol. 2011;186:850–854.
2. Resnick MJ, Lee DJ, Magerfleisch L, et al. Repeat prostate biopsy and the incremental risk of clinically insignificant prostate cancer. J Urol. 2010;77(3):548–552.
3. Pinsky PF, Crawford ED, Kramer BS, et al. Repeat prostate biopsy in the Prostate, Lung, Colorectal and Ovarian cancer screening trial. BJU Int. 2007;99:775–779.
4. Auprich M, Augustin H, Budäus L, et al. A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second, and third repeat biopsy. BJU Int. 2011;109:1627–1635.
5. Jones JS. Managing patients following negative prostate biopsy. Renal & Urology News. 2011:10:23.
ADDITIONAL READING
• Elshafei A, Li YH, Hatem A, et al. The utility of PSA velocity in prediction of prostate cancer and high grade cancer after initially negative prostate biopsy. Prostate. 2013;73(16):1796–1802.
• Levy DA, Jones JS. Management of rising prostate-specific antigen after a negative biopsy. Curr Urol Rep. 2011;12(3):197–202.
• Presti JC. Management of patients with persistently elevated PSA level and negative biopsy. AUA Update Series. 2012; Lesson 1, Volume 31.
• Scott JG, John G, Eric K, et al. Emotional consequences of persistently elevated PSA with negative prostate biopsy. Am J Cancer Prevention. 2013;1(1);4–8.
See Also (Topic, Algorithm, Media)
• PCA3 (Prostate Cancer Gene 3 Urine Assay)
• Prostate Biopsy, Infections and Complications
• Prostate Cancer, General
• PSA Elevation, General Considerations
• PSA, Free and Total
• PSA, General Considerations
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 601.9 Prostatitis, unspecified
• 790.93 Elevated prostate specific antigen [PSA]
ICD10
• C61 Malignant neoplasm of prostate
• N41.9 Inflammatory disease of prostate, unspecified
• R97.2 Elevated prostate specific antigen [PSA]
CLINICAL/SURGICAL PEARLS
• Threshold for repeat biopsy should be low if atypia seen on initial biopsy.
• PCA3 can elucidate the need for further biopsy in those with prior negative biopsy and persistently elevated PSA.
• Emerging imaging modalities are promising in detecting CaP not found on initial PB.