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Screening

Screening considerations

• Who benefits: only screen if life expectancy > 10yrs (UCSF ePrognosis) to see the benefits of cancer diagnosis and treatment, otherwise do not screen
• Prostate cancer mortality: overall lifetime risk is 3%, screening reduces relative risk of mortality by 30%, actual lifetime risk by 1% (down to 2%)
• 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
• Black ancestry: 2x higher risk for mortality than white patients, also earlier age of onset and higher risk for metastatic disease at time of diagnosis
• Family history: no standard definition, consider positive if brother, father, or 2+ male relatives with prostate cancer diagnosis before 60yo, metastatic prostate cancer, or death from prostate cancer, also patients with family history consistent with Lynch syndrome
• Single elevation: PSA will normalize in 25-40% patients on second PSA
• DRE: likelihood of diagnosing clinically significant prostate cancer increases as PSA rises, PPV 4-11% if PSA 0-2.9, 33-85% if PSA 3+
• Screening interval: usually q1-2yr, depends on patient age and PSA (see below)

Age-specific recommendations

• What is considered "normal?": < 2.5 in 40s, < 3.5 in 50s, < 4.5 in 60s, < 6.5 in 70s and 80s
• Age < 40: do not screen, risk of clinically-significant cancer < 0.1%
• Age 40-45: offer screening only if strong family history prostate cancer, family history germline mutation, or Black ancestry (higher prevalence aggressive cancers)
• Age 45-49: can offer screening, if PSA < 0.68 then metastatic 25yr risk is 0.85%
• Age 50-69: screen after discussing risks/benefits, consider screening q2-4yrs, very low risk if PSA < 1
• Age > 70: do not screen unless good life expectancy, recommend stop screening if PSA < 3 (low risk for mortality)
• Family risk: if 1st degree relative with prostate cancer, screen 10yrs earlier than relative's age at diagnosis

Prostate cancer 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 effect/benefits, most commonly studied are 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
• Intercourse/ejaculation: 10% risk of causing PSA rise, if concerned then repeat after abstaining from ejaculation for 48hrs
• 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
• Transient increase: cystoscopy, catheterization, UTI, biopsy
• No proven effect: DRE (unless aggressive), bike riding, long plane/car ride, dialysis (can affect free PSA)
• 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

• Indications: can be offered in biopsy-naive patients, as of 2023 AUA guidelines not yet a clear recommendations
• PIRADS score: scored 1-5, based on T2, DWI, DCE, and 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)

Biopsy 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
• Transrectal technique: make sure needle passing proximal to dentate line to minimize pain

Biopsy recommendations

• Volume: measured as 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, perform at least two biopsies per target and no more than three
• Systematic vs targeted: best results when both are performed
• Risk Calculators: consider using MSKCC, PCPT, or PBCG to calculate risk of finding high-grade (GG2+) cancer on 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, 10-20% are GG2+), recommend 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
• Negative initial biopsy: continue screening with PSA, consider MRI, biomarkers, and risk calculator discussion prior to repeat biopsy

Risk Classification and Genetic Testing

AUA Guidelines Risk Classification

Risk Group	Grade Group	Clinical Stage	PSA	% Cores Positive	Further Workup	Treatment Recommendations	Metastatic risk on surveillance
Low	GG1	cT1-T2a	< 10	-	None	Active Surveillance (unless high risk for progression)	~3% @ 10-15yrs
Intermediate Favorable	GG1 + cT2b-c + PSA < 10 + < 50% positive cores				*	RALP +/- PLND XRT Active surveillance (select patients) Focal therapy	> 10-20% @ 15yrs
	GG1 + cT1-T2a + PSA 10-20 + < 50% positive cores
	GG2 + cT1-2a + PSA < 10 + < 50% positive cores
Intermediate Unfavorable	GG1 + PSA 10-20 + cT2b-c + < 50% positive cores				*	RALP + PLND XRT + ADT
	GG2 +/- PSA 10-20 +/- cT2b-c +/- < 50% positive cores
	GG3 + PSA < 20 + cT1-2c + any cores
High	GG4-5	cT3-T4	> 20	Any cores	CT +/- MR PET scan Consider genetic testing	RALP + PLND XRT + ADT ADT only (palliative option)

*Indications/Notes for Further Staging after Diagnosis

• AUA: CT and bone scan not recommended for low/intermediate risk, obtain bone scan and CT/MR for high risk
• PSMA: recommended for newly-diagnosed high risk localized disease (some recommend for unfavorable intermediate), also can use to assess for biochemical recurrence
• Bone scan: moving towards second line testing compared with PSMA, 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

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