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Screening

Screening considerations

• Who benefits: only screen if life expectancy >10-15yrs (UCSF ePrognosis) to see the benefits of cancer diagnosis and treatment, otherwise do not screen
• Mortality: overall lifetime risk is 3%, screening reduces relative risk of mortality by 30%, actual lifetime risk by 1%
• Incidental cancer prevalence: 0-31% for 20-39yo, 13-55% for 40-59yo, 32-83% for 60-79yo, 48-87% for ≥ 80yo
• Safe PSA level: no PSA threshold at any age that definitively rules out prostate cancer
• DRE: PPV 4-11% if PSA 0-2.9, 33-85% if PSA 3+
• Screening interval: usually q1-2yr, depends on patient age and PSA

Age-specific recommendations

• Age < 40: do not screen, risk of clinically-significant cancer < 0.1%
• Age 40-55: only screen if family history or African-American (higher risk for clinically significant cancer)
• Age 55-70: screen after discussing risks/benefits, consider screening q1-2yrs (q4yrs if PSA < 1)
• Age > 70: do not screen unless good life expectancy, recommend stop screening if PSA < 3, consider biopsy only if PSA > 10
• Family risk: if 1st degree relative with prostate cancer, screen 10yrs earlier than relative's age at diagnosis

Prevention

• Smoking: increases risk for high stage/grade cancer, metastasis, biochemical recurrence, and mortality, smoking cessation decreases risk for aggressive features
• Diet supplements: no proven benefit to any, mostly studied with Vitamin E, selenium, Vitamin C, Vitamin D, soy, omega-3
• Mediterranean diet: possibly some benefit to preventing aggressive types
• Medications: no proven benefits, mainly studied in 5ARi (PCPT and REDUCE trials)

PSA

Elevated PSA differential

• Organ specificity: specific for the prostate, but non-specific for prostate disease, elevation can be cancer, BPH, or prostatitis
• Infection: seen with prostatitis/cystitis, antibiotics may cause PSA drop in 30% men with chronic prostatitis
• Intercourse/ejaculation: 10% risk of causing PSA rise, if concerned then repeat after abstaining from ejaculation for 48hrs
• DRE: elevates PSA slightly, rarely causes false positive results (unless performed aggressively)
• 5ARi: obtain baseline PSA prior to treatment, variable reduction in PSA, multiply by 2.3 after 2yrs and 2.5 after 7yrs, no difference between 1mg and 5mg finasteride dose
• Prostate pressure: elevation seen with massage, cystoscopy, catheterizationbike riding, motorcycle riding, long plane/car rides
• Dialysis: no effect on total PSA level but can affect free PSA

PSA density

• Prostate cancer is more dense than BPH
• PSAd > 0.15: increased likelihood of cancer diagnosis
• PSAd < 0.08: lower likelihood of cancer diagnosis
• Elevated density has sensitivity/specificity of 75%/44% for predicting cancer on repeat biopsy

Prostate Biopsy and MRI

Prostate MRI

• Optional to obtain before biopsy, not yet a recommendation
• PIRADS score: compares T2, DWI, DCE, ADC phases (requires contrast)
• False negative: 10-16% chance of missing clinically significant cancer (negative MRI may still need biopsy)
• Inadequate results if obtained within 6-8 weeks of biopsy (inflammation/bleeding)
• Clinically significant cancer: PPV 17-23%, 34-49%, 67-77% for PIRADS 3, 4, 5
• PROMIS trial (Ahmed 2017): all men underwent standard and saturation biopsy + mpMRI, mpMRI (vs standard TRUS bx) showed increased sensitivity (93% vs 48%) and NPV (89% vs 74%) but decreased specificity (41% vs 96%) and PPV (51% vs 90%)
• PRECISION trial (Kasivisvanathan 2018): either had standard or MRI targeted biopsy, targeted biopsy had higher detection rate of clinically significant disease and lower detection of insignificant disease
• Prostatitis: incidental finding (Class IV prostatitis), not predictive of patient symptoms or outcomes for cancer or LUTS treatments (Hemal 2021)

Patient optimization

• Anesthesia: inject lateral to prostate along neurovascular bundle, or at junction of SVs and prostatic base
• Antibiotics: fluoroquinolones +/- cephalosporin (any generation) or aminoglycoside
• Anticoagulation: do not neede to discontinue ASA 81, but all other anticoagulants need to be stopped or bridged
• Enema: improves imaging but does not affect infection rates

Biopsy recommendations

• Volume: W x L x H x 0.5, normally 20-25g if < 50yo, 45-50g if 60-70yo
• Systematic biopsy: 12 biopsies provides greatest benefit with least risk
• Targeted biopsy: obtain if palpable nodule or MRI lesion
• Make sure needle passing proximal to dentate line to minimize pain
• Risk of finding high grade cancer on prostate biopsy
• Transperineal biopsy: improved anterior and apical tumor detection rates, minimal infection risk
• PIRADS 5 + PSAd > 0.15 (Tafuri 2021): targeted biopsy (without systematic biopsy) has neglible effect on prostate cancer diagnosis, however may miss cancer in contralateral lobe, which may affect focal therapy planning
• Overall findings: false negative rate 30%, including 5% false negative rate if apical zone not adequately sampled
• Cancer risk with negative biopsy: per Kawa 2022, prostate cancer-specific mortality 1.9% at 15yr if negative initial biopsy (vs 37.6% other causes), 13.% 9f PSA < 10, only 12% re-biopsy found GG 2-5
• Erectile function: may see slight decrease in function at 1mo post-biopsy, but should resolve within 3 months (per Fainberg 2021)

Biopsy risks

• Contraindications: coagulopathy, immunosuppression, acute prostatitis, anal stenosis
• Pain: temporary, treat w/ OTC meds, use ice pack behind scrotum
• Bleeding: expected hematospermia in 10-70%, hematuria in 14-50%, ~1% require hospitalization/transfusion, severe bleeding raree but may require sclerotherapy, epinephrine, angiography, and sutures
• Infection: overall rates 0.1-7%, sepsis rates 0.3-3.1%, hospitalization rate 0.6-4.1%
• Vasovagal response: seen in 1-5%, place in trendelenburg and give IV hydration if able
• Urinary retention: seen in 0.2-0.4%, may require temporary catheter

Specific biopsy findings

• Acinar cancer: normal/common variant, > 95% patients have this type
• Prostatic intraepithelial neoplasia (PIN): cellular dysplasia but basal cell layer present, can be confused with ductal/intraductal cancer
• HGPIN: seen 4-5%, repeat biopsy at 1yr only recommended for multifocal HGPIN (30% chance of finding prostate cancer)
• Atypical small acinar proliferation (ASAP): increased cancer risk (40-60% on repeat biopsy), repeat biopsy within 3-6 months, sample specifically from adjacent areas
• Ductal cancer: rare, considered Gleason 4+4, grows into urethral lumen and causes voiding symptoms, PSA often normal, may metastasize to lung, liver, testis, penis
• Intraductal cancer: spread of acinar into the ducts, indicates aggressive variant
• Post-treatment findings: 30% decreased size after ADT, 21% decreased side after 5ARi, edema with brachytherapy, smooth tapering of bladder neck to urethra after prostatectomy

Risk Classification and Genetic Testing

Risk Group	Grade Group	Clinical Stage	PSA	# Cores Positive	% Core Involvement	PSA Density	Further Workup	Treatment Recommendations	Metastatic risk on surveillance
Very Low	GG1	cT1-T2a	< 10	< 1/3	< 50%	< 0.15	none	Active Surveillance	< 1% @ 10-15yrs
Low				-				Active Surveillance (unless high risk for progression)	~3% @ 10-15yrs
Intermediate Favorable	GG1 GG2	cT2b-c	10-20 <10				*	RALP +/- PLND XRT +/- ADT	> 10-20% @ 15yrs
Intermediate Unfavorable	GG2 GG3	cT2b-c	10-20 < 20				*	RALP + PLND XRT w/o ADT
High	GG4-5	cT3-T4	> 20				CT +/- MR bone scan Consider genetic testing	RALP + PLND XRT + ADT ADT only (palliative option)

*Indications/Notes for Further Staging after Diagnosis

• AUA: stage w/ MR/CT if 2/3 are present - palpable nodule on DRE, GG2-3, PSA > 10
• NCCN: stage if life expectancy > 5yrs, get bone scan if cT2 + PSA > 10, get CT if T2 and nomogram predicts > 10% nodal involvement
• Bone scan: if PSA < 10 then NPV 99.5% (do not order), if PSA < 20 then < 1% will have positive bone scan, but PSA > 50 then > 35% will have positive bone scan
• 4K: checks PSA + free PSA + intact PSA + HK2, beneficial after rising PSA, abnormal DRE, or negative biopsy
• Oncotype: tests biopsy specimen to help with risk stratification
• PSMA: new scan very sensitive/specific for untreated and recurrent prostate cancer, indications still evolving, access is still site-specific

Genetic testing (from Weider's 6th edition)

• Homologous recombination repair genes: ATM, BRCA1/2, CHEK2
• DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2
• Germline testing indications: high risk localized disease, regional/distant metastases, ductal/intraductal/cribiform pattern, multiple family members with GG2+ disease, family members with prostate cancer mortality, Ashkenazi jewish ancestry, family history germline mutation, family history Lynch syndrome cancers
• N1M0: consider testing for homologous recombination repair genes or mismatch repair genes
• Castrate naive, M1: recommend testing for homologous recombination repair genes, consider testing for mismatch repair genes
• Castrate resistant, M1: recommend testing for homologous recombination repair genes and mismatch repair genes
• Low/intermediate risk with good life expectancy: testing may help predict risk for progression on surveillance
• Post-RALP with positive margin, pT3, or rising PSA: Decipher helps predict who is best managed with surveillance vs aXRT
• Somatic testing of benign tissue: benign biopsy but high suspicision for prostate cancer, ConfirmMDx or Mitomic Prostate Core Test can predict risk of prostate cancer