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Prostate Cancer
Laboratory Support for Screening, Diagnosis, and Management
Clinical Focus

Clinical Background [return to contents]

Prostate cancer is the most commonly detected cancer in men in the United States, affecting approximately 1 out of every 6 men.1 It is the second leading cause of cancer death among men in the United States.1 Although prostate cancer is thought to begin when men are in their thirties and forties, it is most often diagnosed in men over 65 years of age. Prevalence increases with increasing age.1 

Prostate cancer typically progresses slowly over the course of 15 or more years. When organ-confined, it is potentially curable by radical prostatectomy or radiation therapy (ie, external-beam radiation or brachytherapy). Such therapy, however, may be associated with significant morbidity, including urinary incontinence and impotence. For patients with a good prognosis, watchful waiting may be a better alternative. For metastatic disease, therapeutic options include androgen ablation, adjuvant hormone-radiotherapy, or chemotherapy. Prognosis for patients with metastatic disease is poor, nonetheless.

Laboratory testing can assist with screening, diagnosis, staging, prognosis, detection of residual or recurrent disease, and therapeutic monitoring. The primary test used for these purposes is prostate specific antigen (PSA). PSA is an androgen-regulated, kallikrein-like serine protease produced by normal and malignant epithelium in the prostate as well as in the breast and salivary glands. When secreted into seminal fluid, PSA liquifies the gel-forming proteins in semen. The normal function of PSA in breast and salivary glands is not known.

Individuals Suitable for Testing [return to contents]

Screening

  • Men ≥50 years of age who have a life expectancy of ≥10 years

  • African-American men and men who have a first-degree relative diagnosed with prostate cancer before age 65 (begin screening at 45 years of age)

  • Men who have 2 or more first-degree relatives diagnosed with prostate cancer before age 65 (begin screening at age 40)

  • Men who would be candidates for active treatment if a potentially curable prostate cancer diagnosis was established; candidacy based on age, comorbidity, and an interest in being treated

Patients should be actively involved in the decision to undergo prostate cancer screening and should be fully informed of the potential benefits, limitations, and risks associated with screening. Screening is not recommended for the general population.

Other Applications

  • Symptomatic men

  • Men with a prostate cancer diagnosis

  • Men who are undergoing or have completed prostate cancer therapy

Test Availability [return to contents]

Laboratory tests that can be used to support screening, diagnosis, and management of prostate cancer are listed in Table 1.

Table 1. Laboratory Tests for Screening, Diagnosis, and Management of Prostate
Cancer
Available Tests Method Description

Primary Tests

Free PSA

Total PSA

PSA Post-prostatectomy

PSA Post-prostatectomy  with HAMA Treatment

 

ICMA

ICMA

ICMA

ICMA

 

Includes free, total, and % free/total PSA

Analytical sensitivity: 0.1 ng/mL

Analytical sensitivity: 0.01 ng/mL

Analytical sensitivity: 0.01 ng/mL; eliminates interference from human anti-mouse antibodies (HAMA) that may be present in patients who have received mouse monoclonal antibody preparations

Secondary Tests

bcl-2

DNA Cell Cycle Analysis

E-cadherin

FISH, Prostate Cancer

 

IHC

Flow cytometry

IHC

FISH

 

Detects bcl-2 expression in tissue

Includes ploidy status and % S-phase in tissue

Detects E-cadherin protein in tissue

Detects 8p22 (lipoprotein lipase [LPL]) deletion, chromosome 8 aneusomy, 8q24 (C-MYC gene) gain, 7q31 deletion, and chromosome 7 aneusomy

Ki-67 (MIB-1)

p53 Oncoprotein

Testosterone, Total

IHC

IHC

LC/MS/MS

Detects MIB-1 protein in tissue

Detects mutated p53 oncoprotein in tissue

Suitable for measuring the low levels of testosterone associated with gonadotropin-releasing hormone analogs and antiandrogen therapies

ICMA, immunochemiluminometric assay; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization;

LC/MS/MS, liquid chromatography, tandem mass spectrometry.

Test Application [return to contents]

Screening

Prostate cancer screening remains controversial. Proponents point to the high incidence, absence of preventive agents, ease of screening, potential curability of organ-confined disease, and lack of effective therapy for advanced disease. Opponents tout the slow progression of many tumors, high number of false positives, overdiagnosis of indolent disease, and treatment side effects that lead to diminished quality of life. Since screening commenced in the late 1980s, incidence of metastatic disease has decreased, while the incidence of organ-confined, moderately differentiated disease has increased.2 This suggests screening has been effective in identifying clinically significant, potentially curable disease while reducing the incidence of incurable disease. Mortality has decreased as well,3 but this reduction may be due to factors other than screening and early detection.4 Results from the first randomized controlled trial to show direct evidence that screening reduces prostate cancer mortality have been controversial.5 Two more studies addressing this issue are ongoing; their expected completion dates are between 2006 and 2010.6,7

Pending additional data, the American Cancer Society8 and the American Urological Association9 have recommended that digital rectal exam (DRE) and total PSA be offered annually to men ≥50 years of age who have a minimum life expectancy of 10 years. Screening is recommended earlier (eg, age 40 to 45 years) for African-American men and those with an affected first-degree relative. These organizations also encourage patient education to facilitate informed decision-making, as do the American College of Physicians10 and the American College of Preventive Medicine.11 The latter groups do not support routine screening, nor does the U.S. Preventive Services Task Force.12

Contrary to those of other organizations, the new National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend offering PSA testing (baseline) to all men beginning at age 40 years. Follow-up recommendations (PSA or PSA and DRE at specified frequency) then depend on the PSA concentration and patient age, life expectancy, and risk of prostate cancer. Furthermore, the NCCN strategy incorporates use of free PSA and PSA velocity (see next section, Diagnosis) when making decisions to biopsy men with a total PSA level <10.0 ng/mL.13

Diagnosis

Prostate cancer diagnosis begins with DRE and total PSA. If either is suggestive of cancer, a transrectal ultrasound (TRUS)-guided biopsy is generally the next step (Figure 1). Investigators have attempted to reduce the number of unnecessary biopsies (ie, enhance the specificity of total PSA testing) without reducing the cancer detection rate. To this end, age-specific PSA reference ranges have been proposed as well as calculations of the prostate specific antigen density (PSAD), PSA velocity, and the percentage of free to total PSA (% free PSA). Although conflicting studies have been published regarding the benefit of these strategies, guidelines for use and interpretation are provided herein for physicians who want to use them.

Age-related Reference Ranges

Serum PSA levels increase with increasing age and prostate size in healthy men. Use of age-related reference ranges (Table 2) theoretically would increase sensitivity in younger men and increase specificity (reducing unnecessary biopsies) in older men. Use of age-related reference ranges has not been widely adopted due to studies demonstrating diminished sensitivity in older men.18 Some investigators support the use of age-specific ranges only in men younger than 60 years of age.19

Table 2. Age- and Race-specific Reference Ranges

Age

Years

Free PSA14

(ng/mL)

Complexed PSA14

(ng/mL)

Total PSA (ng/mL)

Causasians15

African-Americans16

Asians17

40-49

<0.5

<1.0

<2.5

<2.0

<2.0

50-59

<0.7

<1.5

<3.5

<4.0

<3.0

60-69

<1.0

<2.0

<4.5

<4.5

<4.0

70-79

<1.2

<3.0

<6.5

<5.5

<5.0

PSA Density
Use of PSAD combines total PSA level with prostate gland volume to assess the probability of a positive biopsy. It is defined as the total PSA divided by the prostate gland volume as determined by TRUS. Levels ≤0.15 ng/mL/cm3 have been associated with a low likelihood of prostate cancer. PSAD has not been widely used owing to lack of consistent evidence regarding clinical benefit.

PSA Velocity
In individuals with pre-clinical prostate cancer, there is an accelerated increase in serum PSA levels, beginning 7 to 9 years prior to diagnosis. Thus, evaluation of the rate of change in PSA levels (PSA velocity, PSAV) may assist in early detection of cancer. Carter et al found that PSA velocity more accurately detected prostate cancer (sensitivity 72%, specificity 90%) than total PSA (sensitivity 78%, specificity 60%).20 As mentioned above, NCCN guidelines incorporate use of PSAV in the early detection of prostate cancer. The guidelines suggest prostate biopsy be performed when the PSAV is ≥0.75 ng/mL/y in men with PSA <10.0 ng/mL. Furthermore, the guidelines recommend using PSAV to monitor men who have had a negative biopsy.13 Instructions for calculating PSAV are provided in Appendix 1.

% Free PSA
Since the overlap in total PSA levels is substantial among men with benign prostatic hyperplasia (BPH) and prostate cancer, use of % free PSA may help distinguish BPH from cancer. PSA circulates in both free and bound, or complexed, forms. Immunoreactive PSA is primarily bound to the α1-antichymotrypsin (ACT) protease inhibitor; thus, PSA levels in healthy individuals mainly reflect complexed PSA. Individuals with benign prostatic hypertrophy (BPH) tend to have lower proportions of complexed PSA (ie, higher % free PSA) relative to those with prostate cancer. Studies using % free PSA (Table 3) have shown improved specificity in men with borderline total PSA levels (4.1-10.0 ng/mL), resulting in a 13% to 37% reduction in negative biopsies. Furthermore, in men with “normal” PSA levels (2.6 to 4.0 ng/mL) use of % free PSA may increase the sensitivity of PSA by detecting cancers that would have been missed by total PSA alone.22,25 NCCN guidelines now approve use of % free PSA to determine need for biopsy in selected men with PSA levels in the 4.1–10.0 ng/mL or 2.6–4.0 ng/mL range.13

Table 3. Improved Specificity with % Free PSA
Reference Free PSA
Cut Point (%)		 Sensitivity
(%)		 Negative Biopsies
Avoided (%)

Catalona WJ, et al22

27a

 90 18

Catalona WJ, et al23

25b

 95 20

Luderer AA, et al24

25b

 100 31

Roehl KA, et al25

25c

 85 19

Van Iersel MP, et al26 

25b

 90 25

Vashi AR, et al27

24b

 95 13

Catalona WJ, et al28

23b

 90 30

Catalona WJ, et al29

23b

 90 31

Bangma CH, et al30

20b

 89 37

a Total PSA 2.6–4.0 ng/mL.

b Total PSA 4.1–10.0 ng/mL.

c Total PSA 2.6–4.0 ng/mL; using a cut point of 30%, sensitivity was 93% but only 9% of negative biopsies could be avoided.

Staging
Tumor staging provides prognostic information and assists in selection of the therapeutic modality. In general, total PSA levels increase with increasing stage, although there is significant overlap (Table 4). A combination of markers has proved to be more useful than any single marker. Nomograms using patient-specific clinical (TNM) stage, biopsy data (eg, Gleason score), and pretreatment total PSA level are commonly used.32 Data from various imaging techniques (eg, bone scan) can also be used.

Table 4. Relation Between Total PSA Concentration and Localized Disease31
PSA ng/mL

Likelihood of Organ-confined Cancer (%)
<4.0 85
4.0–10.0

67
10.1–20.0

56
>20.0

30

Prognosis
The College of American Pathologists (CAP) and the World Health Organization (WHO) both recommend routine use of PSA as a prognostic factor in conjunction with TNM stage, Gleason score, and surgical margin status.33 The NCCN also recommends incorporating PSA levels when determining prognosis.34 The American Joint Committee on Cancer (AJCC), however, excludes inclusion of PSA as a prognostic factor pending evaluation of survival data from multiple institutions.

PSA Kinetics
PSA kinetics are becoming more accepted for predicting disease-free survival, prostate cancer-related mortality, and local vs distant disease at time of biochemical relapse. These predictions are then used to help select appropriate therapeutic regimens.

The same PSAV used in the diagnosis of prostate cancer (see previous discussion) can be used to predict disease-free and cancer-related survival, irrespective of treatment. The cut points for interpretation, however are different; see Table 5 for the cut point used when determining prognosis. PSAV calculated from PSA levels obtained after primary therapy (eg, radical prostatectomy or radiotherapy) can help predict the extent of the recurrence (ie, local vs distant). The guidelines for interpretation are listed in Table 5.

PSA doubling time (PSADT) is the time required for total PSA levels to double. Instructions for calculating PSADT are provided in Appendix 2. Similar to PSAV, PSADT calculated using PSA concentrations obtained before diagnosis can be used to predict survival. PSADT calculated using PSA levels obtained after primary therapy can be used to predict both survival and the extent of the recurrence (Table 5).

The time to biochemical recurrence, following primary therapy (eg, radical prostatectomy or radiation therapy), provides prognostic information regarding the extent of the recurrence (local vs distant) (Table 5). Following radical prostatectomy, biochemical recurrence is defined as a persistent rise in total PSA ≥0.2 ng/mL.35 Following radiation therapy, biochemical recurrence is defined as 3 consecutive rises in PSA levels at least 3 months apart.36 The date of biochemical recurrence is defined as the midpoint between the post radiation nadir PSA and the first of the 3 consecutive rises.

Other laboratory tests that may assist with prognostic assessments are listed in Table 6.

Table 5. Guidelines for Use of PSA Kinetics in Making Treatment Decisions21,37-41
PSA Kinetic Result Clinical Significance
PSADT

Pre diagnosis

 <18 mo Decreased cancer-related survival

After primary therapy

<3 mo

≥10 mo

<10 mo

Decreased cancer-related survival

Recurrence likely to be local

Recurrence likely to be distant

PSAV

Pre diagnosis

>2.0 ng/mL/y

Decreased disease-free survival

Decreased cancer-related survival

After primary therapy

<0.75 ng/mL/y

>0.75 ng/mL/y

Recurrence likely to be local

Recurrence likely to be distant

Time to biochemical (PSA) recurrence after primary therapy

>2 y

≤2 y

Recurrence likely to be local

Recurrence likely to be distant

PSADT, PSA doubling time; PSAV, PSA velocity.

Table 6. Test Results Associated with Unfavorable Prognosis
Test Result

7q31 deletion

8p22 deletion

8q24 gain

bcl-2

Chromosome 7 aneusomy

Chromosome 8 aneusomy

DNA ploidy

E-cadherin

Ki-67 (MIB-1)

p53 mutation

Present

Present

Present

Overexpressed

Present

Present

Aneuploid, tetraploid

Underexpressed

Overexpressed

Present

Initial Treatment Selection
PSA levels can be helpful in making initial treatment decisions when used in combination with TNM-stage, Gleason score, and life expectancy. Cut points most frequently used for such decision-making are 10 ng/mL and 20 ng/mL.9,34 PSA levels <20 ng/mL are associated with negative bone scans, and PSA levels <10 ng/mL are associated with local disease.

Therapeutic Monitoring, Residual and Recurrent Disease Detection
For patients being “treated” with expectant management or watchful waiting, total PSA should be performed every 6 months if life expectancy is ≥10 years.34 If life expectancy is <10 years, PSA testing should be performed every 6 to 12 months. Following definitive therapy, ultrasensitive PSA levels help detect residual disease or document eradication of the tumor (Figure 2). Absence of rising PSA levels is the best indicator of total tumor eradication.43 A 6-month testing interval for the first 5 years followed by annual testing thereafter is suggested for recurrent disease detection following curative treatment.34 For patients with metastatic disease, PSA testing should be performed every 3 to 6 months.34

Sample Collection Considerations [return to contents]

Serum PSA levels are affected by the relatively long half-life (2-3 days) of total PSA and various other factors. The adverse effects of many of these factors can be reduced or eliminated with proper timing of sample collection (Table 7). Furthermore, 3 analyses, each obtained from a separate collection, are recommended prior to biopsy to rule out effects of physiologic and assay variation.48

Table 7. Recommended Timing of Sample Collection44-47
Factor Effect on PSA Level Recommended Timing of Sample Collectiona

Cystoscopy

None or small ↑

Prior to, or 24-48 hours after, procedure

DRE

None or small ↑

Prior to the procedure

Ejaculation

↑

≥48 hours after ejaculation

Prostate biopsy

↑

Prior to, or 4-6 weeks after, biopsy

Prostate massage

2-fold ↑

Prior to the procedure

Prostatitis

↑

8 weeks after end of treatment

TRUS

None or small ↑

Prior to, or 24-48 hours after procedure

TURPb

↑

Prior to, or ≥6 weeks after, surgery

Urethral catheterization

None

Anytime

Urinary retention

↑

≥4 days after relief

DRE, digital rectal exam; TRUS, transrectal ultrasonography; TURP, transurethral resection of prostate.

a To reduce or eliminate effect on PSA level.

b Includes electrovaporization techniques.

Test Interpretation [return to contents]

Total PSA levels >4.0 ng/mL are generally considered elevated, although lower cut points are sometimes used in younger men13 (Table 2). Elevated levels are associated with BPH, acute urinary retention, urinary tract infections (including acute prostatitis), prostatic intraepithelial neoplasia, and prostate cancer. Transient elevations may be observed following DRE, ejaculation, prostate biopsy, or surgery (Table 7).

A 50% or greater change in serial PSA levels is considered clinically significant.46 Decreases in PSA not related to prostate cancer can be caused by medication and herbal supplementation (Table 8).

Table 8. Pharmacologic Effects that Confound Interpretation of PSA Test Results9,49-53
Medication/Supplement

Clinical Indication

Effect on Total PSA

Finasteride

Male pattern hair loss (Propecia®′)

BPH (Proscar®′)

50% ↓ after 6-12 monthsa,b

Dutasteride (Avodart®′)

BPH

~50% ↓b

Terazosin

BPH

None

Antiandrogens (eg, flutamide, bicalutamide, megestrol

acetate)

Prostate cancer

≥50% ↓ for 3-14 months after

withdrawal of medication

Saw palmetto (Serenoa repens)

Herbal supplement for BPH and lower urinary tract symptoms

Possible ↓, similar to finasteride

a May vary widely in individual men.

b % Free PSA not affected.

Screening and Diagnosis
Similar to other screening programs (eg, mammography), two-thirds of screened individuals with an elevated total PSA (>4.0 ng/mL) do not have prostate cancer (66% false-positive rate); however, most of the cancers that are detected are clinically localized (92%) and pathologically organ-confined (64%) and thus potentially curable.54 Approximately 90% are clinically significant tumors, being 1 cc or greater in size.22

Total PSA levels ≤4.0 ng/mL do not guarantee the absence of prostate cancer in asymptomatic individuals; 25% of men with cancer have a PSA level in this range. Indeed, there is no level of PSA at which clinically significant cancer does not occur (Table 9). Consequently, some proponents of screening recommend lowering the PSA cut point to 2.6 ng/mL56 and using % free PSA to reduce unnecessary biopsies. NCCN has recently adopted such a strategy.13

Table 9. Prevalence of Prostate Cancer in Men with PSA Levels <4.0 ng/mL55
PSA ng/mL

Prevalence (%) of Prostate Cancer

0–0.5

 7

0.6–1.0

 10

1.1–2.0

 17

2.1–3.0

 24

3.1–4.0

 27

Among patients with borderline elevated PSA levels (4.1-10.0 ng/mL), approximately 25% will have cancer. Levels >10.0 ng/mL are associated with extracapsular cancer that is less likely to be curable.

Since free PSA is usually eliminated by the kidney, % free PSA can be increased in men with chronic renal failure and in those receiving dialysis. It can also be increased by DRE, prostate biopsy, and prostatectomy. False elevations can occur if the sample is collected prior to 48 to 72 hours after prostate manipulation.

Staging and Prognosis
 Table 4 provides the risk of organ-confined prostate cancer associated with various concentrations of total PSA. Refer to Table 5 for suggested PSAV and PSADT cut points used to assign risk of local vs. distant recurrence and disease-free and cancer-related survival. Table 5 also includes a cut point based on time to PSA recurrence that predicts local vs. distant disease.

Therapeutic Monitoring, Residual and Recurrent Disease Detection
Following successful radical prostatectomy, total PSA levels should be undetectable. A persistent rise in total PSA (≥0.2 ng/mL35) is suggestive of biochemical recurrence, which can precede clinical recurrence by ≥5 years.

Following successful radiation therapy, PSA does not always reach undetectable levels; however, a nadir of 0.5 to 1.0 ng/mL is considered favorable. Biochemical failure after radiotherapy is defined as 3 consecutive rises in PSA levels at least 3 months apart.36

Following successful antiandrogen therapy, there is an initial drop in PSA to normal or even undetectable levels. Relapse caused by androgen-independent tumor cells is characterized by castration levels of testosterone (<50 ng/mL) and 3 consecutive rises in PSA levels 2 weeks apart. Two of these increases should be 50% over the nadir level. Use of PSA for monitoring therapy in individuals with androgen-independent cancer is limited; however, a ≥50% decline from pretreatment levels is considered a sign of a better outcome, relative to a <50% decline, when maintained for 8 weeks.57

Additional interpretive information is provided in Table 10.

Table 10. Interpretation of Test Results13,20,23,25,35,43,55,58,59

Test

Result

Clinical Significance

Free PSAa

 

 

>30% of total PSA

21-30%

11-20%

1-10%

When total PSA is 2.6 to 4.0 ng/mL, probability for prostate cancer is:

20%

19%

25%

43%

  

   

When total PSA is 4.1-10.0 ng/mL, probability of prostate cancer is:

≥26% of total PSA

8%

Biopsy not recommended

21-25%

16-20%

11-15%

16% }
20% }

28% }

Indeterminant; consider other
factors before deciding to biopsy

0-10%

   

56%

  

Biopsy recommended

  

PSA velocityb

<0.75 ng/mL/year
≥0.75 ng/mL/year

  

Low likelihood of prostate cancer

Suspicious for cancer; consider biopsy

  

Total PSAc

   

≤4.0 ng/mL

4.1–10.0 ng/mL

>10.0 ng/mL

20.0–29.9 ng/mL

≥30 ng/mL

         

Likelihood of prostate cancer:

15%

27%

59%

74%

96%

   

PSA, Post Prostatectomy

<0.01 ng/mL

Undetectable level of PSA; absence of recurrence
<0.10 ng/mL

Low likelihood of residual or recurrent cancer post radical prostatectomy

≥0.2 ng/mLd

Residual or recurrent cancer likely after radical prostatectomy

0.5-1.5 ng/mL

Consider 2nd line treatment with radiotherapye

a Not helpful in 2/3 of all men, ie, those who have % free PSA between 10% and 25%.

b See Table 5 for cut points associated with survival and local vs distant disease prognosis.

c See Table 9 for prostate cancer prevalence associated with PSA ≤4.0 ng/mL.

d NCCN guidelines recommend >0.3 ng/mL and rising on 2 or more measurements.34

e Initiate radiotherapy in patients with post prostatectomy recurrence while PSA is ≤1.5 ng/mL for best therapeutic response.

Appendix 1. PSA Velocity (PSAV) Calculations

PSAV can be calculated using linear regression.21 Alternatively, calculate PSAV using 3 consecutive PSA measurements20:

1. PSAV = [PSAt – PSAt-1] ÷ [yeart – yeart-1] where t is the most recent PSA level and t-1 is the

previous, consecutive measurement.

2. Average PSAV = [PSAVt + PSAVt-1] ÷ 2 where t is the most recent PSAV and t-1 is the previous,

consecutive PSAV.

Always use PSA measurements from a minimum of 3 samples collected over at least 18 months. Furthermore, all PSA test results should be generated using reagents and method from the same manufacturer.

Appendix 2. PSA Doubling Time (PSADT) Calculations

PSADT can be calculated using one of the following 2 methods42:

1. PSADT = natural log of 2 (ie, 0.693) ÷ slope of the line derived from a plot of log[PSA] vs time

of PSA measurement.

2. PSADT = (natural log of 2)(time interval) ÷ (log[final PSA] – log[initial PSA]) where the time

interval is the period between initial and final PSA measurements.

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Content reviewed 11/2009