The 5 Minute Urology Consult 3rd Ed.

PSA ELEVATION, GENERAL CONSIDERATIONS

Leonard G. Gomella, MD, FACS

Adam P. Dicker, MD, PhD

 BASICS

DESCRIPTION

• PSA is used for diagnosis and treatment of prostate cancer (CaP). This section reviews the use of PSA in the diagnosis of CaP recognizing that screening is an area of controversy

• CaP is only diagnosed through tissue biopsy and not by PSA alone

• Normal PSA level is controversial, and can be elevated due to malignant or benign causes.

– Elevated PSA traditionally >4.0 ng/mL based on the Baltimore Longitudinal Study of Aging

 Specificity 91%, sensitivity 21% (51% for Gleason ≥8), PPV 30%

– Elevated PSA >2.5 ng/mL has support

• Age/race-specific proposed, but controversial:

• Based on Prostate Cancer Prevention Trial (biopsy regardless of PSA), can have CaP with “low” PSA. No lower cutoff or normal PSA to indicate absence of cancer. PCPT data:

• The challenge: Lower normal PSA to recommend biopsy where life-threatening cancer is present, but not to point where “overdetection” of incidental (autopsy/insignificant CaP) occurs

• PSA derivatives may overcome problem, but not absolute: Used in PSA range of 4.0–10 ng/mL: PSA density (PSAD), PSA velocity (PSAV), newer PSA assays (free, molecular forms)

• PSA changes over time more useful than a single PSA in screening for CaP

• A single PSA of >1.3 ng/mL before age 50 predicts increased lifetime CaP risk (1)

• PSA >10: More risk of advanced disease.

• PSA proportional to prostate volume; prostate volume/mean PSA were as follows: 14 cm3/1; 25 cm3/1.13/52 cm3 1.45 in 1 study

ALERT

PSA should not be done with acute prostatitis or within 3–4 wk of prostate instrumentation: false-positive risk.

EPIDEMIOLOGY

Incidence

• Across all races, age >50, only 7.9% of men randomly screened have PSA >4.0 ng/mL

• Median PSA: 4th decade, 0.7 ng/mL; 5th decade, 0.9 ng/mL 6th decade, 1.3 ng/mL; 7th decade, 1.7 ng/mL

Prevalence

US CaP approximately 2,106,499 men, or 1.5% all ages and races

RISK FACTORS

• For elevated PSA

– Advancing age

– Benign prostatic hypertrophy (BPH)

– CaP

– Infection, infarction

– Recent instrumentation (TURP, cystoscopy, catheterization, prostate biopsy)

• CaP (See chapter “Prostate Cancer, General”)

Genetics

• PSA associated with kallikrein genes family (long arm of chromosome 19 region q13.2–q13.4).

• PSA is also called human kallikrein 3 (hKLK3)

PATHOPHYSIOLOGY

• PSA: A serine protease produced by the prostatic epithelium and periurethral glands that liquefies seminal coagulum

• Seminal fluid has high PSA concentrations (mg/mL); PSA is much lower (ng/mL) in serum

• Many forms of serum PSA: Free PSAs (nicked, intact, several forms of proPSA) and complexed PSA (bound to protease inhibitors α1-antichymotrypsin [ACT], α2-macroglobulin [MG], α1-protease inhibitors [API]); bound PSA forms stable complex (no serum enzymatic activity) (2)

– 60–90% complexed to ACT; free portion is also detected by assay, while that bound to MG is not detected by routine assay

– Complexed PSA: Hepatic clearance (1/2-life 2.2 days); FPSA cleared by glomerular filtration (1/2-life 2–3 hr)

• CaP PSA elevation is due to disrupted prostatic architecture and compromised integrity of the basal layer or basement membrane

– CaP makes less PSA/g than benign tissue

• Androgens influence PSA levels

• Sources of fluctuation in PSA:

– No PSA analytic standard; can vary by lab and use same lab to compare serial values

– 15% coefficient of variation in PSA assay

– Physiologic variation in PSA 15–30% in the short term; BPH can vary up to 30%

– 26–37% with elevated PSA return to normal 1 yr later, and 45–55% normal within 4 yr

– Seasonal variation: PSA is higher in summer

– Infection, infarction, trauma, ejaculation within 24 hr, or prostate instrumentation or massage can produce elevations (not routine DRE)

– Finasteride (5 mg BPH; 1 mg alopecia) and dutasteride are 5α-reductase inhibitors; lower PSA by 50% over 6 mo; “correct” PSA by doubling to maintain PSA utility

ASSOCIATED CONDITIONS

• BPH

• Acute and chronic bacterial prostatitis

• Urinary retention

GENERAL PREVENTION

• None for CaP

• Avoid PSA measurement when false-positive elevation likely (See “Risk Factors” above)

• Use same lab/assay for serial measurements

 DIAGNOSIS

HISTORY

• Difficulty with urination, such as hesitancy, straining, weak stream, or intermittency

• Dysuria, frequency, or urgency

• Previous PSA levels or prostate biopsies

• Family history of prostate carcinoma

• Medications, including herbals

• Markedly elevated PSA >20 ng/mL with bone, back, or hip pain suggests metastatic CaP

PHYSICAL EXAM

• DRE: Nodules, induration, asymmetry, bogginess, tenderness (Note: American Cancer Society recommends PSA screening with or without DRE)

• Adenopathy, supraclavicular

• Bony pain, point tenderness with metastasis

• Neurologic: Lower extremity strength/sensation

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Routine UA to rule out UTI/prostatitis (1 – 3)

• Consider evaluation for prostatitis by modified Stamey–Meares test or exam of EPS (See Section I: Prostatitis, Chronic, Bacterial [NIH II])

• Consider %FPSA (FPSA/TPSA or F/T PSA)

– With CaP lower FPSA; postulated that CaP produces more ACT

– FPSA best with TPSA 4.0–10.0 ng/mL and prostates <50 g; not useful if TPSA >10 ng/mL

– FPSA stratifies CaP risk on biopsy (table) (3)

• Consider PSAD: PSA ÷ TRUS volume:

– Correlates PSA to TRUS prostatic size to distinguish BPH from CaP:

– Useful with PSA 4–10 ng/mL and a previous negative biopsy

– Cutoff of 0.15 ng/mL/cm3 improves specificity by 50%, missed 27–48% CaP

– Cutoff 0.1 avoids 31% of biopsies, misses 10% cancers; cutoff of 0.8 avoids 12% of biopsies, misses 5% of cancers

• Consider PSAV:

– Rate of PSA increase; PSA rises more rapidly if clinically significant CaP present:

– Minimum 18-mo interval with ≥3 repeat PSAs for most accurate PSAV determination.

 PSA1 = 1st PSA (ng/mL)

 PSA2 = 2nd PSA (ng/mL)

 PSA3 = 3rd PSA (ng/mL)

 Time1 = time between PSA1 & PSA2 (yr)

 Time2 = time between PSA2 & PSA3 (yr)

– Baltimore Longitudinal Study: 72% CaP had PSA rise >0.75 ng/mL/yr vs.10% with BPH

– PSAV > 0.35 predicts PCa death w/ PSA <4

– PSAV >0.75 90–100% PCa sensitivity w/ PSA >4

– PSA velocity >02 in year before dx predicts PCa mortality

• “Prostate Health Index” or phi assay

– CaP low FPSA, increased % proPSA

– Calculation ([–2]proPSA/FPSA) × √TPSA

– phi 27–55, CaP 9.8–50%, Gl ≥7 3.9–28.9%; phi 27: 18.8% could be spared biopsy (low risk)

Imaging

• TRUS: Determine prostatic size; PSAD; most useful to guide systematic needle biopsy

• Multiparametric MRI with/without endorectal coil: Useful if CaP suspicion and negative biopsy. Anterior tumors and other sites can be identified

• CT or bone scan: No role in CaP screening

Diagnostic Procedures/Surgery

• TRUS-guided prostate biopsy with 18G biopsy needle and local anesthesia:

– Systematic biopsy (12 cores) with laterally directed samples is now standard for CaP.

Pathologic Findings

See Section I: “Prostate Cancer, General.”

DIFFERENTIAL DIAGNOSIS

• Adenocarcinoma of the prostate (CaP)

• BPH

• Prostatitis (usually bacterial infection)

• Prostatic infarction: Idiopathic or after shock

• Iatrogenic: Recent cystourethroscopy, Foley catheter placement, prostate biopsy

• Prostatic massage (but not routine DRE)

• Trauma (cycling, extensive)

• Ejaculation within 24 hr of PSA test (rare)

 TREATMENT

GENERAL MEASURES

• Shared decision making before PSA based CaP screening in asymptomatic patients

• Due to PSA fluctuations, confirm an elevated PSA with a 2nd reading before biopsy. Patient should not ejaculate for 48 hr before test.

• Review serial PSA determinations for PSAV

• CaP screening recommendations:

– See Appendix for ACS, ACP, EAU, NCCN, USPSTF

• AUA 2013 CaP Early Detection Guideline (4):

– No PSA screening in men under age 40 yr

– Does not recommend routine screening between ages 40 and 54 yr at average risk

– Shared decision-making for men 55–69 yr considering PSA screening due to risks/benefits; proceed based on a man’s values and preferences

– To reduce harms, screening intervals of 2 yr preserves the benefits and reduces overdiagnosis and false-positives

– No routine PSA screening in men age 70+ yr or <10–15-yr life expectancy; but some 70+ yr in excellent health may benefit from screening

• Some published prostate biopsy indications:

– Prostate nodule, regardless of PSA

– PSA >10 ng/mL in the absence of prostatitis

– PSA >4.0 ng/mL and PSAV >0.75 ng/mL/yr

– PSA <4.0 ng/mL and PSAV >0.3–0.5 ng/mL/yr

– PSA >2.5 ng/mL and PSAV >0.60 ng/mL/yr

– PSA 4–10 and F/T PSA<10%

– F/T PSA <20% and PSAV >0.75 ng/mL/yr

• Numerous assays under study to help differentiate benign form malignant PA elevation (See Section II: “PSA, General Considerations.”)

MEDICATION

First Line

• Empiric antibiotics for elevated PSA is no longer recommended by most sources

• With bacterial prostatitis, treat and repeat PSA 4 wk after: Fluoroquinolone (eg, ciprofloxacin 500 mg BID.) or TMP-SMX (180/800 mg BID)

Second Line

N/A

SURGERY/OTHER PROCEDURES

If patient has anorectal pathology, consider transperineal prostate biopsy for CaP diagnosis

ADDITIONAL TREATMENT

• CaP risk calculators are available on the Internet to predict outcome of biopsy.

• PCA3 urine testing after attentive DRE; FDA approved only after initial negative biopsy; PCA3/TMPRSS2-ERG urine test investigational

Additional Therapies

Any PSA rise while on finasteride/dutasteride baseline raises CaP risk

Complementary & Alternative Therapies

No evidence for herbals effect on PSA

 ONGOING CARE

PROGNOSIS

• With elevated PSA, positive biopsy rate is about 25–30%; elevated PSA and nodule 18–60%

• Overall, if 2nd biopsy is performed after initial negative, detection rate is 10–35%.

COMPLICATIONS

Failure to diagnose cancer; patient anxiety over repeat testing; risk of biopsy and drugs

FOLLOW-UP

Patient Monitoring

• There is no single threshold PSA which should prompt prostate biopsy. Biopsy decision based on PSA, DRE, and multiple factors (F/T PSA, age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history, comorbidities, patient preferences) (5).

• PSA <2.5 ng/mL, low PSAV: Annual DRE/PSA

• PSA 2.6–10 ng/mL, low PSAV:

– Consider biopsy or obtain FPSA

– F/T PSA >25%: Repeat PSA/DRE in 6 mo

• Based on TRUS biopsy results:

– Negative: Repeat DRE/PSA in 6 mo; consider F/T PSA as guide for another biopsy

– HGPIN or ASAP:

 Repeat biopsy (3–6 mo); consider transition zone sampling with any repeat biopsy.

– Positive biopsy (CaP): Staging studies, discuss treatment options

• Persistent PSA elevation (PSA >10 ng/mL)

– Repeat biopsy; transition zone sampling; multiparametric MRI of TRUS/MRI fusion biopsy

Patient Resources

AUA Urology Care Foundation. http://www.urologyhealth.org/urology/index.cfm?article=68

REFERENCES

1. Lilja H, Cronin AM, Dahlin A, et al. Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50. Cancer. 2011;117(6):1210–1219.

2. Shariat SF, Semjonow A, Lilja H, et al. Tumor markers in prostate cancer I: Blood-based markers. Acta Oncol. 2011;50(suppl 1):61–75.

3. Catalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative biopsies. J Urol. 1997;158:2162–2167.

4. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. J Urol. 2013;190(2):419–426.

5. Greene KL, Albertsen PC, Babaian RJ, et al. Prostate specific antigen best practice statement: 2009 update. J Urol. 2013;189(1 suppl):S2–S11.

ADDITIONAL READING

Heidenreich A, Abrahamsson PA, Artibani W, et al. Early detection of prostate cancer: European Association of Urology recommendation. Eur Urol. 2013;64(3):347–354.

See Also (Topic, Algorithm, Media)

• Prostate Cancer Screening Guidelines

• Prostate Cancer, Biochemical Recurrence (Elevated PSA) Following Cryotherapy

• Prostate Cancer, Biochemical Recurrence (Elevated PSA) Following Radiation Therapy

• Prostate Cancer, Biochemical Recurrence (Elevated PSA) Following Radical Prostatectomy

• Prostate Cancer, General

• PSA Elevation Following Negative Prostate Biopsy

• PSA, General Considerations

 CODES

ICD9

• 185 Malignant neoplasm of prostate

• 600.00 Hypertrophy (benign) of prostate without urinary obstruction and other lower urinary tract symptom (LUTS)

• 790.93 Elevated prostate specific antigen [PSA]

ICD10

• C61 Malignant neoplasm of prostate

• N40.0 Enlarged prostate without lower urinary tract symptoms

• R97.2 Elevated prostate specific antigen [PSA]

 CLINICAL/SURGICAL PEARLS

• Routine DRE will not clinically significantly elevate PSA.

• PSA 1/2-life is 2.2 days; may remain elevated for up to 4 wk after instrumentation.



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