Prostate Cancer - PSA

Indications for Testing

Follow up previously elevated PSA (screening recommendations can be found in the Screening section)
New prostate nodule or hypertrophy

Laboratory Testing

PSA

4-10 ng/mL – indeterminate; consider PSA free percentage, PSA velocity (PSAV) testing, or PCA3
>10 ng/mL – recommend biopsy
<3 ng/mL – repeat PSA in 1 year
Normal PSA values do not rule out prostate cancer (substantiated by the Prostate Cancer Screening trial); age-specific reference ranges should not be used for PSA

PSA values and associated risk of developing cancer

PSA Value	Risk of Developing Cancer
<0.5 ng/mL	6.6%
0.6-1.0 ng/mL	10.1%
1.1-2.0 ng/mL	17%
2.1-3.0 ng/mL	23.9%
3.1-4.0 ng/mL	26.9%

PSA can be elevated in benign conditions

PSA free percentage
- Premise – the ratio of free (unbound) PSA to total PSA is reduced in prostate cancer
- Free PSA expressed as a percentage of total PSA – both values need to be measured concurrently
- Most useful for PSA concentrations 4-10 ng/mL with normal digital rectal exam (DRE) (Sturgeon, 2008)
- Risk is age-dependent – the older the patient and the lower the percentage, the higher the risk for prostate cancer
- PSA free percentage >25% – associated with low risk (considered normal)
- PSA free percentage ≤10% – associated with >50% risk, regardless of age
- PSA free percentage <25% – consider biopsy based on clinical circumstance
PSAV
- Premise – PSAV increases more rapidly in men with prostate cancer
- Defined as rate of increase in PSA over time
  - PSAV = (PSA test #2-PSA test #1)/time elapsed
- Requires at least 3 serial measurements (Noguez, 2014)
- Biopsy may be considered based on individual risk factors if PSAV result is ≥0.35 ng/mL/year and PSA concentration is >2.6-4 ng/mL (National Comprehensive Cancer Network [NCCN], 2015)
PSA density (PSAD)
- Premise – prostate cancer is more dense than benign conditions
- PSA divided by ultrasound volume of prostate gland (using transrectal ultrasound)
  - Normalizes for large glands that produce increased amounts of PSA
- Higher value (typically >0.1-0.15 ng/mL) associated with increased risk of cancer

PCA3 (urine)

Premise – PCA3 is overexpressed in prostate cancer but not in benign hypertrophy
PCA3 is a prostate-specific noncoding mRNA
Aids in decision for rebiopsy of individuals >50 years who have had
- One or more negative prostate biopsies AND
- For whom a repeat biopsy would be recommended by a urologist based on current standard of care (FDA, 2012)
May reduce rate of rebiopsy (Wei, 2014)
Specimen
- Collect urine sample after DRE
Test methodology
- In vitro nucleic acid amplification test
- Utilizes
  - Target capture transcription-mediated amplification
  - Hybridization-protection assay for amplicon detection
- PCA3 score – calculated as the ratio of PCA3 RNA copies to PSA RNA copies, multiplied by 1000
Sensitivity and specificity
- 77.5% and 57.1% respectively – relative to prostate biopsy outcome
- Based on a PCA3 score cut-off value of 25

PCA3 scoring results interpretation

PCA3 Ratio	Result	Interpretation
0-17	Negative	Associated with decreased likelihood of a positive biopsy for prostate cancer
18-24	Negative	Interpret with caution – due to normal test variability, specimens with PCA3 scores near the cut-off may yield a different overall interpretation upon repeat testing
25-31	Positive	Interpret with caution – due to normal test variability, specimens with PCA3 scores near the cut-off may yield a different overall interpretation upon repeat testing
>31	Positive	Associated with increased probability of a positive biopsy for prostate cancer

Histology

Sonographically guided biopsy for tissue sample recommended if
- PSA >10 ng/mL
- PSA is 4-10 ng/mL with a free percentage <25%
Biopsy results determine subsequent recommendations
- Atypical small acinar proliferation – repeat PSA and DRE in 3 months
- High-grade intraepithelial dysplasia (PIN 3) – repeat PSA and DRE in 3 months and every 3 months for 1 year
- Malignancy detected – recommendations as per urologist
Immunohistochemistry (Epstein, 2014)
- P504S (AMACR); p63; cytokeratin 5/6; keratin 903 (high molecular weight)
- ARUP’s PIN4 prostate triple stain includes most relevant markers – P504S, p63, 34βE12
Molecular testing
- BRCA1 and BRCA2 gene testing should be considered
  - For aggressive prostate cancer (Gleason ≥7) diagnosed at any age
  - If ≥2 close relatives with breast, ovarian, aggressive prostate, or pancreatic cancer at any age

Genetic Testing

Genetic testing should be considered (ACMG, 2015)
- For aggressive prostate cancer (Gleason ≥7) diagnosed at any age and ≥2 close relatives with breast, ovarian, aggressive prostate, or pancreatic cancer at any age
- ≥2 cases of prostate cancer at ≤55 years in close relatives
- ≥3 first degree relatives with prostate cancer

Prognosis

Future risk of cancer
- Baseline PSA above median for age (40-55 years) is a strong predictor of future cancer risk
Current cancer
- Higher initial PSA concentration correlates with increased risk of tumor progression over 10 years and with metastatic disease at the time of future diagnosis
- Aggressive tumor behavior is suggested by
  - Higher PSAD (>0.10-0.15)
  - Higher PSAV (>2 ng/mL/year)
  - High Gleason score

Differential Diagnosis

Prostatitis – bacterial, fungal, Mycobacterium tuberculosis
Benign prostatic hypertrophy

Prostate Cancer Screening Algorithm

Read more about Prostate Cancer Screening Algorithm

Existing evidence from randomized trials does not support routine screening for prostate cancer (Croswell, 2011)
- Most societies except for USPSTF, ACPM, and AAFP recommend shared decision-making with age, life expectancy, and risk factors to determine when to start screening
- Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO], 2014 – no difference in overall survival between 76,693 screened and unscreened patients
- European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, 2014 – no difference in overall survival between 162,243 screened and unscreened patients
  - Significant improvement in survival with screening but at high risk for overtreatment
PSA is the main tumor marker for prostate cancer screening
- Prostatic acid phosphatase (PAP) is not recommended

Screening recommendations

Society	Age to start screening	Who to exclude	Screening frequency	PSA
AAFP (2012)	AAFP recommends against PSA-based screening for prostate cancer	n/a	n/a	n/a
ACP (2013)	55 yrs with shared decision making 45 yrs – African American, men with 1^st degree relative with prostate cancer at <65 yrs 40 yrs – multiple family members diagnosed at <65 yrs	Patient ≥70 yrs Patients with life expectancy <10-15 yrs	Consider longer intervals (>1 yr)	n/a
ACPM (2008)	Insufficient evidence to recommend routine population screening with DRE or PSA	n/a	n/a	n/a
ACS (2010)	50 yrs – average risk 45 yrs – African American, men with 1^st degree relative with prostate cancer at <65 yrs 40 yrs – multiple family members diagnosed at <65 yrs	Patient <50 yrs	Annually in conjunction with DRE if PSA ≥2.5 ng/mL; biannually if PSA <2.5 ng/mL	Use PSA free percentage test in cases where total PSA 4-10 ng/mL (2.5-10 ng/mL may be preferred in some cases) No interpretive guidelines available for PSA free percentage when total PSA is <2.5 ng/mL or >10 ng/mL
ASCO (2012)	Men with life expectancy >10 yrs	n/a	n/a	n/a
AUA (2013)	55 yrs – average risk Higher risk patients – individualize approach and consider earlier age to screen	Patient >65 yrs with life expectancy <10-15 yrs Patient ≥70 yrs of age	Every 2 yrs in conjunction with DRE	Use PSA free percentage test only in cases where total PSA 4-10 ng/mL (2.5-10 ng/mL may be preferred in some cases) No interpretive guidelines available for PSA free percentage when total PSA is <2.5 ng/mL or >10 ng/mL
EAU (2013)	40-45 yrs	Patient <50 yrs – exception for patients who have a first-degree relative diagnosed with prostate cancer <65 yrs Patient >65 yrs with life expectancy <10 yrs Patient >75 yrs – average life expectancy at 75 is <10 yrs	Intervals every 2-4 yrs for PSA >1.0 ng/mL and up to 8 yrs if PSA <1 ng/mL at baseline screen	n/a
ESMO (2015)	Population based screening is not recommended	Patients >70yrs
NCCN (2015)	50 yrs (average risk)	Patient <50 yrs – exception for patients who have a first-degree relative diagnosed with prostate cancer <65 yrs Patient >65 yrs with life expectancy <10 yrs Patient >75 yrs – average life expectancy at 75 is <10 yrs	Annually in conjunction with DRE	n/a
USPSTF (2012)	Screening should not be offered (Grade D recommendation)	n/a	n/a	n/a
ACP = American College of Physicians; ACS = American Cancer Society; ASCO = American Society of Clinical Oncology; AUA = American Urological Association; EAU = European Association of Urology; ESMO = European Society for Medical Oncology; NCCN = National Comprehensive Cancer Network; USPSTF = U.S. Preventive Services Task Force

PSA concentrations – recommended for monitoring disease progression, active surveillance
- Every 6 months is adequate for most patients
- Successful surgical resection should lead to PSA concentrations <0.05 ng/mL
  - Radiation therapy may not result in concentrations equally low
- Subsequent rise in concentrations is indicative of residual disease, metastasis, or PSA bounce
Circulating tumor cell count (CTC)
- Use in metastatic tumors in conjunction with clinical data and imaging to monitor response to therapy and disease progression
- Cutoff point – >5 CTCs/7.5 ml of blood
- Independent predictor of progression-free survival and overall survival
- Subsequent rise in concentrations is indicative of residual disease or metastasis
DRE – as often as every 6 months, but at least every 12 months

Prostate cancer is the most frequent malignant neoplasm in men and the second most common cancer death among American men.

Epidemiology

Incidence – >233,000 in 2014 (American Cancer Society, 2014)
Age – risk rises steeply with age
- <50 years – low risk
- ≥65 years – 75% of cases
Sex – exclusively male
Ethnicity – higher occurrence in African Americans

Risk Factors

African American ethnicity
Family history – 5- to 11-fold increase in risk with a first-degree relative diagnosed with prostate cancer at <65 years
Older age
BRCA1 or BRCA2 mutation

Pathophysiology

Tumors are usually adenocarcinomas that depend on androgens for growth
Epithelial cells of prostate produce prostate-specific antigen (PSA) and acid phosphatase
- Production also increased with tumors and also with inflammation and hyperplasia – lacks specificity for diagnosis of cancer
Most tumors develop in peripheral zone of prostate, commonly in the posterior aspect

Clinical Presentation

Frequently asymptomatic
Signs and symptoms of enlarged prostate – urgency, frequency of urination, nocturia
Metastatic disease
- Bone pain – pelvis, spine most common sites
- Osteoblastic lesions are on imaging

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Prostate Specific Antigen, Total 0070121
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Preferred initial screening test used with DRE

May use to monitor patients for recurrence of cancer

Limitations

Results from different assay methods or kits cannot be used interchangeably

Elevated PSA concentrations only suggest the presence of prostate cancer; biopsy confirmation required

False-positive results occur in benign prostatic hyperplasia and inflammatory conditions (eg, prostatitis)

Follow-up

DRE and TRUS

Serial measurements of PSA required

Prostate Specific Antigen, Free Percentage (Includes Free PSA and Total PSA) 0080206
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

May provide additional prostate cancer risk information for patients with mildly elevated total PSA and a negative DRE

Percentage of free PSA to total PSA

Alternative to PCA3 testing in indeterminate PSA cases (4-10 ng/mL)

Limitations

Results from different assay methods or kits cannot be used interchangeably

Elevated PSA concentrations only suggest the presence of prostate cancer; biopsy confirmation required

False-positive results occur in benign prostatic hyperplasia and inflammatory conditions (eg, prostatitis)

Follow-up

DRE and TRUS

PCA3 - Prostate Cancer Biomarker by Transcription-Mediated Amplification 2010102
Method: Qualitative Transcription-Mediated Amplification

Recommended Use

Aids in the decision of rebiopsy for men ≥50 years who have had one or more negative prostate biopsies AND for whom a repeat biopsy would be recommended by a urologist based on current standard of care

Collect after DRE

Clinical sensitivity/specificity – 77.5% and 57.1% respectively (relative to prostate biopsy outcome), based on a PCA3 score cut-off value of 25

Limitations

Values obtained with different assay methods or kits cannot be used interchangeably

Sufficient number of prostate cells must be present in the urine for analysis

PCA3 testing should not be used for men with atypical small acinar proliferation (ASAP) on their most recent biopsy

Prostate Specific Antigen, Ultrasensitive 0098581
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Do not use for initial prostate cancer screening

Preferred test is total prostate specific antigen in conjunction with digital rectal exam

May be used to monitor disease after radical prostatectomy

Limitations

Results from different assay methods or kits cannot be used interchangeably

Circulating Tumor Cell Count 0093399
Method: Immunomagnetic Separation/Immunofluorescent Stain/Computer Assisted Analysis

Recommended Use

Use for patients with metastatic prostate cancer in conjunction with clinical data and imaging to monitor response to therapy and disease progression

Cutoffs vary by tumor cell type

Limitations

CTC is not as accurate as imaging in assessing whether a patient has progressive disease

Doxorubicin therapy patients – allow at least 7 days following administration of a dose before testing

Not detected – CTCs that do not express EpCAM or CTCs that express EpCAM but not cytokeratins 8, 18, and 19

Serial CTCs should be performed in the same laboratory

PIN4 Prostate Triple Stain by Immunohistochemistry 2010045
Method: Immunohistochemistry

Recommended Use