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PROSTATE CANCER AND PROSTATE SPECIFIC ANTIGEN (PSA)V Srinivas
Consultant Urological Oncologist, PD Hinduja National Hospital, Mumbai, India.
INTRODUCTION
Prostate cancer is the most common cancer in men. In the United States in 1998, about 185,000 new cases of prostatic cancer were diagnosed and about 40,000 patients died due to the disease. The prognosis is excellent for patients with localized tumours, however the mean survival for patients with metastatic disease is about 3 years. In the Western countries, about 60% of patients initially diagnosed with prostatic cancer have localized disease. However, in India about 84% of patients diagnosed with prostatic cancer have advanced disease at the time of diagnosis. [1] It is important to note that the majority of men who die of this malignancy are still active and productive members of the society. Today most investigators dealing with this disease feel that healthy men with a life expectancy above 10 years, diagnosed with localized disease, have a potentially curable malignancy and should undergo some form of curative therapy.
In recent years major efforts have been made to reduce prostatic cancer mortality by detecting the disease at an early, organ confined, stage. This is best achieved through the combination of digital rectal exam and prostate specific antigen (PSA) measurement.
Prostate specific antigen (PSA) is the most important tumour marker available today for the early detection, staging and monitoring of men with prostatic cancer. PSA is a protein manufactured by prostate cells to help maintain semen in liquid form. It was first identified in seminal fluid in 1971. PSA is produced in both normal and cancerous prostatic cells, but the malignant cells generally produce more of the antigen. [2]
Biological characteristics
PSA is a single chain chymotrypsin like, serine protease formed by 237 aminoacids displaying a striking resemblance to the kallikrein family. PSA is synthezied by epithelial cells lining the acini and ducts of the prostate gland. It is then secreted into the prostatic ducts and is present in high concentrations in the seminal fluid. There it liquefies the seminal coagulum at the time of ejaculation because of the chymotrpsin - like enzymatic activity. As the liquefaction of the seminal coagulum progresses, continuous release and activation of the spermatozoa occur.
PSA is found in different molecular forms within body fluids of men. The major portion of PSA in the serum is bound to Alpha 1 anti-chymotrypsin (PSA-ACT). Another portion is bound to alpha-2-macroglobulin (PSA-AMG). A third portion is the so called free (non-complexed) PSA which is unbound. Different assays can quantify Free PSA and PSA-ACT. The half life of PSA ranges from 2 to 3 days. [3]
Role of PSA
Measuring PSA levels allows physicians to detect prostatic cancer so small that it cannot be felt. In general, normal PSA levels are below 4 ng/ml. A reading between 4 and 10 ng/ml indicates about 20% chance that cancer is present and a measurement above 10 ng/ml is considered a strong indication of prostatic cancer. These levels are however not absolute and various factors can influence their effects as will be discussed later.
Elevated or reduced levels of PSA are guidelines only. The test is not an absolute indication for either ruling out or confirming the presence of cancer. The PSA test misses about 25% of all tumours. Conversely 2/3 of the men with marginally increased PSA show no cancer on biopsy. About 25 to 50% of patients with benign prostatic hyperplasia or prostatic infection may show elevated level of PSA but no cancer. Other factors, like prostate needle biopsy may also increase PSA level. Hence, it is very important not to make a diagnosis of prostatic cancer solely on the basis of a raised PSA.
Once cancer is diagnosed, PSA level is also measured to determine its extent. If PSA level is less than 20 ng/ml then it is likely the cancer has not spread. Metastasis is strongly indicated as the level rises over 40 ng/ml.
PSA level is also used for monitoring the course of the disease after initial treatment of prostatic cancer. Rising level indicates recurrence of tumour, although the exact location cannot be determined just by using PSA. In contrast to this, if the PSA falls significantly after treatment and remains persistently low, then it will indicate the disease is under control.
It is important to realise that 35% of men with organ confined prostatic cancer present with normal PSA level. Additionaly about 38% of men who undergo radical prostatectomy present only with a palpable lesion. Thus PSA alone is not the sole test but a combination of PSA and digital rectal examination is more effective in detecting early prostatic cancer. [4]
Concepts for improving PSA
In order to improve the specificity and sensitivity of PSA for the detection of prostatic cancer, different concepts have been introduced including 1) PSA density 2) PSA velocity 3) age specific PSA and 4) percentage free PSA.
PSA density
Malignant prostatic tissue produces high level of PSA compared to an equal volume of benign tissue. In patients who have a PSA in the region between 4 ng/ml and 10 ng/ml, it is difficult to determine whether the rise in PSA is due to benign or malignant disease. In this subgroup of patients, the PSA density is thought to be helpful. The PSA density is basically a ratio between the serum PSA and prostate volume assessed by a transrectal Ultrasound. The normal PSA density is roughly 0.15 and it is helpful in identifying patients who are at a lower risk for having prostatic cancer. However, since the prostate volume is measured by transrectal ultrasound it is examiner dependent and thus often subjective, leading to difficulty in interpretation and standardization of these results.
PSA velocity
PSA velocity is a change in PSA over time and some investigators feel it is more useful than PSA alone in distinguishing between men with and without prostatic cancer. The cut off value of 0.8 ng/ml per year is generally used in measuring PSA velocity. Most authorities have recommended three consecutive measurements over a two year period to determine the PSA velocity. Thus PSA velocity increases the predictive value for the detection of prostatic cancer compared to PSA alone. However, follow-up of at least two year is required before therapeutic decisions can be made.
Age specific PSA levels
The normal PSA range of 0 to 4 ng/ml does not account for age-dependent growth and variations in PSA secretion and production. Many people feel that PSA of 6 ng/ml in a 75 year old man has a different significance than the same value in a 50 year old man. As you grow older, the PSA level rises even if there is no evidence of malignancy. At present no standardized table is available to compare the PSA at different age ranges and a cutoff value of 4 ng/ml is still used at most laboratories. However, in years to come it is conceivable that lower PSA limits may be used in younger patients.
Free PSA
It was mentioned earlier that there are two kinds of PSA circulating in the blood; one is the free PSA and the other is the bound PSA (PSA-ACT). Initial studies have indicated that bound PSA (PSA-ACT) may be higher in men with a prostatic cancer. The ratio of free to total PSA may be used as a tool to improve the differentiation between benign prostatic hypertrophy and malignancy especially in men who have a PSA in the region of 4 to 10. A cut off level for percentage of free PSA in the range of 14 to 18% may be useful in determining the presence or absence of malignancy. However, many laboratories still do not report test results in ratios of free to total PSA and this is still in the standardization stage.
Factors influencing PSA
Drug treatment
The use of Proscar (5 alpha-reductase inhibitor) reduces total PSA level in men without prostatic cancer, by approximately 54%. Thus using the normal PSA referral range in these men without adequate medical histories may lead to false negative results. No studies are yet available showing that simply doubling the PSA value in these men to adjust for PSA level can accurately detect prostatic cancer.
Prostate size
The fact that BPH tissue secretes a considerable amount of PSA means that patients with large, big prostate would have a high PSA level simply because of the volume of benign tissue. These patients may not have any cancer but just a large volume benign prostatic hyperplasia.
Prostatic infections and manipulation
Prostatic inflammation such as prostatitis can result in large increase in PSA levels. Similarly prostate needle biopsies can cause temporary elevation of PSA level. A simple rectal exam usually does not raise the PSA by significant level.
Practical points
- Serum PSA is the most important tumour marker currently available for the diagnosis, staging and management of men with prostatic cancer. The large number of false-positive, false-negative results when PSA is used by itself for the detection of prostatic cancer has led to a surge for other means to improve the sensitivity and specificity of PSA. However, the use of total PSA is still the standard serum test for the early detection of prostatic cancer.
- When a patient presents with a raised PSA and a prostate nodule then a biopsy can be done of the prostate to determine if malignancy is present.
- However, when a patient presents with a raised PSA and a normal feeling prostate, it is essential to give the patient a course of antibiotics and reassess the PSA after a week or ten days to see if the PSA has come down. If the PSA shows a downward trend then the raised PSA was obviously due to some infection and the patient can be spared a biopsy.
- The role of PSA density, age specific PSA and free and total PSA is still considered unstandardized methods and should be used only in the research laboratories and patient treatment should not be dependent on this as yet. Additionally, recent advances such as the discovery of the hereditary prostate cancer gene (HPC-1) may be useful in future to determine subsets of patients who are at a high risk for prostate cancer. [5]
CONCLUSION
At present a yearly PSA evaluation with rectal examination can help in diagnosing prostatic cancer at an early stage resulting in higher cure rates.
REFERENCES
- Srinivas V, Mehta H, Amin A, Choudhary R, Gadgil N, Ravishanker D, Phadke AG. Carcinoma of the prostate-state at initial presentation. International Urol Nephrol 1995; 27 (4) : 419-422.
- Wang MC, Valenzuela IA, Murphy GP. Purification of a human prostate specific antigen. Invest Urol 1979; 17 : 159-63.
- Oesterling JE, Jacobsen SJ, Klee GG. Free, complexed and total serum PSA - The establishment of appropriate reference ranges. J Urol 1995; 154 : 1090-95.
- Walsh PC. Using prostate-specific antigen to diagnose prostate cancer - sailing in uncharted waters. Ann Intern Med 1993; 119 : 949.
- Smith JR, Freije D, Carpten JD. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genomewide search. Science 1994; 274 : 1371-74.
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