What is the recommended course of action for a 51-year-old male with elevated Prostate-Specific Antigen (PSA) levels, a Prostate Imaging-Reporting and Data System (PI-RADS) 3 lesion on Magnetic Resonance Imaging (MRI), and currently taking Testosterone therapy?

Management of 51-Year-Old Male with PSA 4, PI-RADS 3 Lesion, on Testosterone Therapy

This patient requires prostate biopsy with both targeted and systematic sampling, and you should strongly consider temporarily discontinuing testosterone therapy until cancer is definitively excluded. 1

Immediate Action Required

Proceed with prostate biopsy now. The combination of PSA at the traditional threshold of 4.0 ng/mL plus a PI-RADS 3 lesion warrants tissue diagnosis, particularly in a patient on testosterone replacement therapy where PSA may be artificially suppressed or rapidly rising. 1

Why Biopsy is Mandatory in This Case

• PSA of 4.0 ng/mL is the established threshold for biopsy regardless of other factors, as recommended by multiple guidelines including the New England Journal of Medicine monitoring protocols for testosterone therapy. 1

• Men on testosterone therapy may have occult cancers that grow more rapidly upon normalization of testosterone levels, making a lower threshold for biopsy prudent in this population. 1

• PI-RADS 3 lesions carry a 20-43% risk of clinically significant prostate cancer (≥Grade Group 2) when biopsied, which is far too high to observe without tissue diagnosis. 2, 3, 4

• The European Association of Urology 2024 guidelines specifically recommend taking both targeted biopsy of any PI-RADS 3 lesion AND systematic biopsy for optimal cancer detection. 1

Biopsy Strategy

Perform combined MRI/TRUS fusion-guided targeted biopsy of the PI-RADS 3 lesion plus systematic 12-core sampling. 1

• Targeted biopsy alone misses clinically significant cancers, as systematic biopsies detect additional intermediate/high-risk tumors not visible on MRI. 1

• In patients with PI-RADS 3 lesions, systematic biopsies have significantly higher detection rates for clinically insignificant disease, but targeted biopsies are still necessary for the visible lesion. 4

Role of PSA Density in This Case

While PSA density (PSAD) can help risk-stratify PI-RADS 3 lesions, it should NOT be used to avoid biopsy when PSA is already ≥4.0 ng/mL. 1

However, calculate PSAD for prognostic information:

• PSAD >0.15 ng/mL/mL significantly increases the likelihood of clinically significant cancer in PI-RADS 3 lesions (independent predictor on multivariable analysis). 3, 4

• PSAD >0.20 ng/mL/mL is an even stronger independent risk factor for clinically significant disease. 4

• Even with PSAD <0.15, approximately 13.6% of patients with PI-RADS 3 lesions harbor clinically significant cancer—too high a miss rate to safely avoid biopsy. 3

• Some data suggest PSAD <0.10 ng/mL/mL corresponds to only 10% risk of clinically significant cancer in PI-RADS 3 lesions, but this threshold has not been validated in men on testosterone therapy. 5

Critical Testosterone Therapy Considerations

Before Biopsy

Consider temporarily holding testosterone therapy until biopsy results are available, though this is not absolutely required. 1

• The New England Journal of Medicine guidelines state that some experts perform prostate biopsy before initiating testosterone treatment as the most definitive way to exclude cancer, though they acknowledge this may be impractical. 1

• Since this patient is already on testosterone, the priority is obtaining tissue diagnosis now rather than debating whether therapy should have been started. 1

If Biopsy is Negative

Testosterone therapy can be safely continued with appropriate monitoring. 1

• There is no need to withhold testosterone once a negative biopsy result has been obtained, since PSA abnormalities may be due entirely to benign causes. 1

Monitoring Protocol While on Testosterone

Implement heightened PSA surveillance given the baseline PSA of 4.0 ng/mL:

• Repeat PSA every 3-6 months for the first year, then annually thereafter. 1

• Perform repeat biopsy if PSA increases by ≥1.0 ng/mL in any year. 1

• If PSA increases by 0.7-0.9 ng/mL in one year, repeat PSA in 3-6 months and perform biopsy if there is any further increase. 1

• Alternative stricter approach: Some experts recommend biopsy for PSA increase >1.0 ng/mL in the first 6 months of treatment or >0.4 ng/mL/year thereafter in men on testosterone therapy. 1, 6, 7

• Perform digital rectal examination at each monitoring visit. 1

Common Pitfalls to Avoid

Do not use MRI alone to decide against biopsy. A negative or equivocal MRI (PI-RADS 3) is not an indication to forego biopsy when PSA is ≥4.0 ng/mL. 1

Do not assume the PSA elevation is solely from testosterone therapy. While testosterone typically increases PSA by only 0.30-0.43 ng/mL on average, this patient's PSA is at the absolute threshold requiring evaluation regardless of testosterone use. 1

Do not delay biopsy to "watch" the PSA. The combination of PSA 4.0 ng/mL and a visible MRI lesion (even if equivocal) meets established criteria for immediate tissue sampling. 1

Do not perform targeted biopsy alone. Systematic sampling must be included as it detects clinically significant cancers missed by targeted approaches in 6.7% of cases. 1

If Prostate Cancer is Diagnosed

Management depends on grade and extent of disease, but testosterone therapy decisions become more complex:

• Historically, prostate cancer has been considered an absolute contraindication to testosterone therapy, though this is now under debate for men deemed cured after treatment. 1

• Active surveillance may be appropriate for low-risk disease (ISUP Grade Group 1) in selected patients, but patients with cribriform or intraductal histology should be excluded. 1

• Intermediate-risk disease (ISUP Grade Group 2) generally requires definitive treatment, though highly selected patients with favorable features may be candidates for active surveillance. 1