It's now going on a quarter of a century since PSA revolutionized prostate cancer. As most aging and elderly men know by heart, PSA stands for "prostate-specific antigen." It's virtually the one and only immunoassay marking progression of the men-only malignancy.
PSA, the urologist's clinical buddy, is an enzyme 240 amino acids in length, produced by prostatic epithelial cells. It's normally found in seminal fluid and circulating blood - which accounts for the PSA periodic urology test. However, unfortunately, that test tests PSA's presence not only in cancerous cells but in the prostate's commoner camouflage, benign prostatic hyperplasia (BPH). This annoying but not dangerous swelling can mimic carcinoma and prostatitis, the latter being an inflamed but not cancerous prostate gland.
A significant number of elderly patients with cancer confined inside their prostate gland have normal PSA readings, below 4 nanograms per deciliter. Levels above 10 ng/dl strongly spell prostatic carcinoma. Approximately 30 percent of patients with PSA numbers between these two limits will likely have prostate cancer detectable by needle biopsy (sans anesthetic) within one year.
Most men with prostate cancer die of some cause other than that disease. Prostate cancer (PC) progresses slowly as a rule - frequently measured in years - and often with no symptoms. To many patients, the consequences of aggressive therapy, which might bring on urinary incontinence and impotence, seem worse than the disease. PC can be cured by radical surgery (prostatectomy) or radiation therapy, but only if the disease is localized within the prostate gland. If it has spread locally or distantly, no curative treatment is available and these patients will suffer from a poor prognosis.
During the 1980s, the increased use of PSA screening led to an apparent shift in the incidence of prostatic carcinoma, with proportionally more diagnoses in men under 70 and fewer in men over 70 - plus a higher incidence of early or prostate-confined disease. That shift peaked in 1992; incidence data have declined substantially since 1990.
Prostate cancer doesn't kill its victims. It's the metastasis - the spread to bladder, kidney, liver, bone or other organs - that does the lethal work. Annually, 35,000 to 40,000 people in the U.S. die of the malignancy. It's the second-leading cause of neoplastic deaths among U.S. males (after lung cancer), as well as Western European populations. Another estimated 200,000 prostate cancer patients are diagnosed with the malignancy each year in the U.S.
Can 108 Prostate Patients Be Wrong?
What urologists and their prostate patients doubtless wish for is a more precise indicator - say a gene - to trump the unreliable PSA. In fact, a half dozen or more PC genes are under investigation, mainly in Europe, for their potential in diagnosis or prognosis. These are not to be confounded with "bad" mutated PC genes, which are genetically related to familial breast and ovarian cancers.
A paper in the Elsevier journal European Urology for July 2003 suggests that a noninvasive genetic test could soon appear to aid the diagnosis of prostate cancer. The article's title: "DD3PCA3-based molecular urine analysis for the diagnosis of prostate cancer." Its senior author is experimental urologist Jack Schalken at the University of Nijmegen, the Netherlands.
"We studied a cohort of 108 patients admitted for biopsy with serum PSA values above 3 ng/dl," the paper related. "Upon biopsy," it continued, "24 of them were shown to have prostate cancer. Another 16 scored positive for the DD3PCA3 gene - indicating a 67 percent sensitivity. Moreover, the genetic test was nearly 90 percent accurate in confirming negative results. After extensive prostate massage, voided urine samples were collected from among the 108 individuals with PSA levels higher than 3ng/dl, the lower limit. Thus the diagnostic procedure was neither invasive nor expensive.
"The reasoning behind that published test is that the manipulation of the prostate would transport the cancer cells via the prostatic ductal system into the prostatic urethra, the urine's conduit - which is pinched by a swollen prostate. The results were comparable between ejaculate and urethral washings. Therefore, voided urine sample collection was elected since it is a more acceptable specimen for men to give rather than ejaculate. Normal prostate, BPH and tumor specimens were obtained from fresh glands.
"It is expected that future studies will address the issue of detecting malignant prostate cells by DD3 quantitative analysis in ejaculates or blood, even in cases in which tumor specimens contained less than 10 percent of tumor cells. DD3 is the most prostate cancer-specific gene described so far.
"The novel DD3PCA3 gene is strongly overexpressed in more than 95 percent of primary prostate-cancer specimens and in PC metastases. The gene is located on the long arm of human chromosome 9. Furthermore, unlike PSA, its expression is restricted to prostatic tissue."
Genetic Boon For A Practicing Urologist
"DD3 was initially discovered by differential display analysis," the journal article recounted. "The Nijmegen research group reported on its overexpression four years ago in 53 of 56 prostate cancers. It was detected in prostate but not in 18 different normal human tissues, from bladder to testis. These initial findings stimulated further research on DD3 in carcinoma of the prostate.
"For a practicing urologist," Schalken observed, "the most important repercussion of the data from this study is the fact that, on the basis of a noninvasive diagnostic DD3 test, the number of repeated biopsies in patients with PSA levels less than 3ng/dl might be considerably reduced. This genetic test offers great promise as a noninvasive diagnostic tool for the detection of prostate cancer. Future multicenter studies using this test should provide the first basis for the use of molecular diagnostics in clinical urological practice."
An accompanying editorial by Austrian specialist Zoran Culig at the University of Innsbruck made the point: "Although PSA serum measurement identifies an increased number of patients who could be treated by radical surgery, there is still a need to improve diagnostics in early stage prostate cancer. For this reason, current research is focused on identification of prostate- or prostate cancer-specific urinary sediments, obtained after extensive prostatic massages, which has a high negative predictive value. This will have great impact for the reduction of the number of biopsies."