Statistics for screening tests: (1) Prevelance of the disease in the patient-group being tested is a huge factor in the reliability of the test result. When a person considers the implication of a positive test result, a (2) second factor is of GREAT importance, especially in a "free" country where people can still (as of 5/2012) choose a course of action. (1) Depends on group statistics whereas (2) is a statistical universe of one. That is, if a man is 4 feet 10 inches tall and were to play basketball against a man just over 7 feet tall, to make decisions in instance (2) based on the average heights of the two men (6 feet) is irrelevant. So, on 22 May 201211, when the task force recommended no further screening PSA testing on men, that entity used its gravitas to help reduce federal spending & DID NOT act in the best interests of an individual male patient. Other limitations of tests HERE. Especially if age 60 or younger, there is nontrivial risk in failing to take the screening finding seriously, according to this risk-model study13.
Prevelance of prostate cancer: Autopsy series have shown a least small prostate cancers in 29%
of men 30-40 years old and 64% of men 60-70 years old; the lifetime
risk for men for getting prostate cancer (Pca, PCa, PC, or CaP) is
1 in 62. Until the 1980s, this usually-asymptomatic malignancy was not diagnosed until symptomatic and incurable7.
Early detection preserves the broadest array of management choices: The screening use of the PSA test beginning in the mid-1980s has
revolutionized the ability to detect prostate cancer early and has shifted the
stage of the cancers sharply to an earlier stage7. Yet, an early study
showed that nearly half of the expected cancers are not detected (see
table below) by biopsies when the threshold for diagnostic action is between
3 & 3.9 ng/ml2. By 2002, it had become a new conventional
practice to use age-adjusted normal ranges. In 2012, we have saturated the population with screening to the point that active surveillance is now a very legitimate "initial management" decision if it seems that the tumor is an "indolent lesion of epithelial origin" (a so-called IDLE7 tumor). Biomarkers heralding indolence or aggressiveness will become valuable.
Technical: Some argue about
which test method is best; of utmost importance, however, is that
a lab verify and properly control an adequate test system. And, because the multiple test system products may "test" against slightly different PSA forms, it is best if one has testing in the same lab each time. This test
refers most commonly to "total PSA [tPSA]". But be aware1 that
the serine protease PSA circulates in serum in multiple molecular
forms consisting of free (unbound to other proteins) PSA (fPSA) and
various proteins (about 75% is irreversibly bound to the protease
inhibitor alpha-1 antichymotrypsin in a covalent 1:1 molar ratio
that creates an enzymatically inactive complex). And there are other
complexes. Most of free PSA exists as 3 isoforms (BPSA, proPSA, & "intact
PSA parameters used: The tPSA value as a numerator can
be divided by gland volume and thereby relate the tPSA level to gland
size...the calculation producing the "PSA density" or PSAD
(a normal value being less than 0.10 to 0.15...below 0.15 is comforting, 0.15-0.18 is concerning, & 0.18 or higher warrants a biopsy) where values greater
than 0.15 are said to increase the odds that the patient has prostate cancer1. "PSA
velocity" attempts to account for the very steady tendency for
PSA to gradually rise with age and increasing BPH (benign gland enlargement)1; other causes of increasing PSA are cancer or prostatitis.
It is of greatest help when one has at least three tPSA results over
a period of at least 2 years1. One is more concerned
that a rising PSA is due to prostate cancer if the increase is greater than 0.75
ng/mL per year1, the NCCN guideline "normal" being no greater than 0.5 in 20073(and Dr. Catalona expecting in 2007 that this will be reduced to a cutoff of 0.35-0.4 ng/mL/year...noting that there is a high death rate among those with a velocity of 2ng/mL/yr or higher in the year prior to diagnosis3).
EPCA & EPCA-2 apparently failed as reliable tests, HERE.
PCA3 = prostate cancer antigen 3 (a synonym is DD3)(HERE) is coded by the same PCA3 gene; it is a noncoding mRNA over-expressed (increased) in prostate acinar cancer cells (also precancer...PIN...cells?) and causing PCA3 elevation in the test. It is present at about a 34-fold concentration compared to either (1) normal or (2) BPH prostate cells and not present in other tissues or malignancies6. As of mid-2011, we are not completely sure if any other prostate-gland cell abnormalities (such as PIN) cause elevations. So, clear-cut elevations are a significant clue that a man's prostate gland has greater odds of harboring cancer. A normal value does NOT indicate that the gland is cancer free (for many reasons, the cells containing the PCA3 may not have been dislodged or burst by the DRE manipulation & made it into the specimen container). The higher the PCA3 result, the less comforting is a decision toward conservative, active surveilance rather than going ahead with some treatment.
RATIOS for testing: For this PCA3 test and the TMPRSS2:ERG (a topic which follows), a ratio of acinar-cell-related markers is needed so as to adjust for the sampling variables unavoidable by cancers being in different gland locations and differing percentages of gland involvement.
THE SPECIMEN: "PCA3" is usually reported as a simple number (but the lab-reported value is actually as a ratio of PCA3 to PSA, both parameters by mRNA analysis within that specimen of prostatic-fluid-urine mixture from the DRE). While often advertized as a "simple urine test", it is actually a VERY non-simple, limited, first-voided urine immedatey following a specialized digital rectal exam (DRE). Current insider "code words" in some labs call this specialized DRE an "attentive DRE", for the specific purpose of obtaining prostate fluid (with cancer cells) delivered by 3 deep digital strokes of each of the two prostate lobes so that the disrupted cancer-cell-containing intraprostatic fluid is pushed into the bladder with the urine but DOES NOT become too dilute with too much urine. The obtaining office staff (or the lab, if quickly handy) must (1) quickly mix the specimen and pipette two mL into each Aptima-kit transport tube (which contains RNA integrity maintaining & stabilizing transport fluid) & keep refrigerated to the local lab (which may then freeze the tubes for frozen delivery to the out-of-state reference lab) and (2) fill out patient case clinical details listed on the requisition. Our lab sends out through ARUP who currently (as of 2010-2011) uses Avero Diagnostics. (ARUP PSA & PCA3 decision tree here)
TMPRSS2:ERG gene fusion, the most common variant of ETS gene rearrangements in prostate cancer = the TE test specimen is obtained exactly as with PCA3 & tested as a ratio as with PCA35. It holds forth the hope of helping to acurately discern cancer cases OK for active surveilance from those (with significantly elevated TMPRSS2:ERG levels) needing undelayed treatment5. Ventana has produced the corresponding IHC histology marker, ERG, which correlates with the ERG gene rearrangemnet demonstrable by FISH. Nuclear marker, when strong, correlates with lower Gleason score [S13-1417]14. A focus of ASAP is more likle cancer if ERG strong nuclear positivity15. And, this web site (Pathology Outlines) is regularly updated on markers, ERG HERE.
TE Abstract4: "Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy." (Gen-Probe, Inc. has licensed the technology & hopes to offer the test later in 2012.) BUT, a recent review notes sources that say prognostication of aggressiveness of tumor is not that certain8. However, that same review notes value of finding this TE rearrangement (TER), as those with it had an increased rate of death by disease at 12 years of follow up8.
Prostate cancer gene expression profile by rt-PCR: This test uses FFPE prostate biopsy cores, and the test is developed by Health Discovery Corp. and first offered by Clarient and now under world-wide licensing by NeoGenomics. With 90% agreement with expert prostate cancer pathologists, the test supposedly separates prostate cancer cases that are grade 3 or higher from those of lower grade (and possibly of lower risk). If the core biopsies (which seldom represent more than a minute fraction of the cancer in a gland) fail to sample the highest-grade cancerous area in the gland, then a gene-expression-based treatment decision can be sorely discordant and leave patient and physician in a treatment decision quandry and "false negative" as to the worse cancer that had not yet been sampled! Other types of gene expression studies by various molecular techniques continue to be published. The problem with these is that there is no histological morphospecific control on the analytic results to assure that the findings actually came from the cancer cells (molecular analysis info).
Epigenetic cancer periphery changes detection by some sort of methylation testing of extracted DNA is being advertized as of April 2012 in the FFPE samples tested by the ConfirmMDx assay.
Beckman Coulter has just been given FDA approval12 to market its PHI (prostate health index) because of claims that the PHI calculation (total PSA, plus free PSA, plus p2PSA) is 2.5 times more specific in detecting prostate cancer in the elevated total PSA range of 4-10 ng/mL range. I remember similar claims years back when "free PSA" came onto the market. I'm dubious as to any real advantage yet.
The prostate health index (PHI) is a formula that manipulates same specimen results for PSA, free PSA and [-2] proPSA so that "positivity" supposedly indicates prostate cancer (rather than benign PSA elevations) and significant prostate cancer16. We will have to see how this works out.
General: (1) low free PSA, especially < 15%
= concern for ca. (2) higher free PSA, especially > 25% = favor
- ASCP Check Sample...Shariat SF, Roehrborn CG,
Wians, FH, Update on PSA Testing for the Early Diagnosis of
Prostate Cancer, Clinical Chem. 43(5):71-87. 2003.
Schroder FH, Kranse R, Verification Bias and
the PSA Test: Is There a Case for a Lower Threshold for Biopsy?,
NEJM 349(4):393-395. 24 July 2003.
- CAP Today, April 2007.
- Tomlins SA,...Siddiqui J, et. al., "PROSTATE CANCER: Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA", Sci. Transl. Med. 3(94): 94, 3 August 2011, HERE.
- Javed Siddiqui, M. S., personal communications, February 2012.
- Loeb S and Partin AW, Review of the Literature: PCA3 for Prostate Cancer Risk Assessment and Prognostication, Rev Urol.,13(4): e191–e195, 2008, HERE.
- Thompson IM & Klotz L, Editorial: Active Surveillance for Prostate Cancer, JAMA 304(21):2411-12, 1 December 2010.
- Annual Review Issue, Prostate Cancer: Towards the Standardization and Synthesis of Morphology, Genetics, and Prognosis. Kristiansen G,Diagnostic and Prognostic Molecular Biomarkers for Prostate Cancer, 60(1):125-141, January 2012.
- Park K, et. al., "Antibody-Based Detection of ERG Rearrangement-positive Prostate Cancer", Neoplasia 12(7):590-598, July 2010.
- PCA3.org website HERE.
- USPSTF May 2012 PSA screening statement, etc. HERE.
- CAPToday, 28(6):102, August 2012.
- Gulati R, et. al., "Models for Projecting Risk...", Cancer Epidemiol.Biomarkers Prev. 20;740-750, 2011.
- Suh JH, et. al., "EGR immunohistochemistry...", Korean J. Pathol. 46(5):423-8, Oct 2012, HERE.
- He H, et al, "The diagnostic utility of novel immunohistochemical marker ERG in the workup of prostate biopsies with 'atypical glands suspicious for cancer'", Am. J. Surg. Pathol., 35(4):608-14, April 2011, HERE.
- The PHI HERE & it was reviewed in Medscape June 2014.
[to prostate cancer topics index]
(posted 4/27/2007; latest addition 14 June 2014)