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GH7P54LQFUGI
PROSTATE QUEST FOR EARLY
DIAGNOSIS
ANIL BATTA
Introduction:--
Prostate cancer is a frequent cause of death in men.
Unfortunately, the majority of prostate cancers have
spread beyond the gland when first diagnosed using
the conventional detection method, digital rectal
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examination. Prognosis is poor and treatment
options are limited to palliative therapy with late
stage disease. With no curative therapy foradvanced prostate cancer available currently or in the
foreseeable future, the most promising alternative for
improving the prognosis of patients with prostate cancer is
to enhance early detection.
WAY TO DIAGNOSIS EARLY:--
The most useful tumour marker for prostate cancer
at present is prostate-specific antigen (PSA). PSA is
a glycoprotein that is almost exclusively produced in
the prostate. The major forms that presently can be
determined in human serum are the uncomplexed,
free form (f-PSA, MW ~33 kD) and a complex of f-
PSA with E1-antichymotrypsin (MW ~100 kD). Bothforms represent the main fraction of total PSA (t-
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PSA) that can currently be identified in human
serum (1-3).
The determination of prostatic acid phosphatase(PAP) does not add clinically useful information to
PSA measurement, and is therefore not
recommended (4,5).
Screening and diagnosis
The use of PSA for the detection of prostate cancer
leads to an earlier diagnosis and probably more
curable stages of the disease are detected. On the
other hand, knowledge of the natural history of early
lesions suggests that indiscriminate use of PSA will lead
to overdiagnosis and overtreatment in some cases (6).
Information on the effectiveness of treatment is
currently unavailable, and no evidence exists thatearly diagnosis and treatment will lead to an
improvement of disease-related and overall mortality
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(7,8). Despite these uncertainties it is proposed that
use of the PSA test should not be withheld from
symptomatic men and those who wish to beexamined for the presence of prostate cancer.
Application to the general population should depend,
however, on the results of prospective randomized
studies showing that early detection and treatmentcan decrease prostate cancer mortality (9). Since
the positive predictive value (number of positive
tests in patients with the disease divided by the total
number of tests performed) of PSA in screening
populations is disturbingly low (~30%) it is
necessary to enhance the specificity of the tumour
marker (10-13).
URGENCY FOR EARLY TREAMENT:--Possible ways to increase the specificity of t-PSA in
the diagnosis of prostate cancer may include
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determination of t-PSA/prostate volume-ratio (14-
16), use of age-specific reference ranges (17-19) or
measurement of serial t-PSA increase over time (PSA"velocity" or "doubling time") (20-22) but evidence
is as yet inconclusive or the application is of limited
use in daily practice. The use of age-specific
reference ranges cannot be recommended yet, sinceno trials are available showing the efficacy of
prostate biopsies for age-specific PSA decision points
of concentrations lower than 4 ng/ml. For highly
selected sub-populations, the free to total PSA ratio
may hold most promise to enhance the specificity of
PSA for detecting prostate cancer (1-3, 23-27) but
considerable further research is required.
Despite well documented drawbacks, t-PSAdeterminations can be recommended
in symptomatic men, if the diagnosis of prostate
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cancer alters the treatment decision. In the absence
of studies documenting that early detection of
prostate cancer does more good than harm it maybe reasonable to restrict PSA testing
in asymptomaticindividuals to those who agree to
undergo prostate biopsy in case of elevated t-PSA
levels and have a life expectancy of more than tenyears (28, 29). At this time, there is no evidence to
encourage the widespread use of PSA testing or the
introduction of population based screening to detect
prostate cancer (7).
BIOCHEMICAL MARKERS:--
To assure a valid recognition of the presence or
absence of cancer suspicion, the characteristics and
assay-specific reference ranges of available PSA
assays (of which there are now more than eighty)
should be distributed by the producer of the assay.
Every laboratory report should contain the name of
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the assay used and a valid reference range,
specifically generated for thisassaytoenable the
physician in charge ofinterpretingthe resultstodraw correctconclusions(30-32). Ethnicorregional
differencesbetween reference range populations
need tobe considered (33, 34).
Digitalrectalexamination doesnotinfluence theconcentration oft-PSA toaclinicallysignificant
extentin mostofthe studiespublished, butthe
serum concentration off-PSA can probablybe
increased bymanipulation ofthe prostate suchas
digitalrectalexamination (35) orfollowing
ejaculation (36), resultingin "free tototal" PSA
ratiostypicalofthose seen in benign prostatic
hyperplasiain prostate cancerpatients. Toavoid
suchmisleadingresults, blood should be drawn prior
todigitalrectalexamination and the time interval
since the lastejaculation should be noted. Although
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evidence exists that changes in f-PSA concentrations
occur within several hours after drawing of the blood
sample (37-39), no recommendations for theoptimal time interval before processing can be given
currently and it is proposed to use the same pre-
analytical conditions that were applied in generating
the reference values of the assay used (37).Medication with anti-androgenic effect (e.g. LHRH
agonists or 5-alpha-reductase inhibitors) can lead to
low t-PSA concentrations although prostate cancer is
present.
EARLY DIAGNOSIS & TREATMENT:-
Following the diagnosis and treatment of prostate
cancer, t-PSA is a valuable tool for determining the
prognosis of a patient in the absence of anti-androgen treatment. If anti-androgen treatment has
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been initiated, t-PSA does not always reflect the
behaviour of the tumour.
Knowledge of post-treatment t-PSA values can
enhance quality of life if they indicate absence of
residual disease, but conversely can lead to
diminished well-being in otherwise asymptomatic
patients who can anticipate the clinical progress of
the disease by rising t-PSA values months or even
years prior to the appearance of symptoms. The
possible drawbacks of t-PSA determinations
following treatment should always be weighedagainst the therapeutic means that can be offered to
the patient in case of rising t-PSA values.
f-PSA has not been shown to offer clinically relevant
prognostic information and should therefore not bedetermined during follow-up of prostate cancer (40).
BRIEF CONCLUSION:--
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t-PSA is clearly the best marker available for
prostate cancer but must be used in conjunction
with digital rectal examination. Although almosttissue-specific, it is not disease-specific. There is
considerable overlap in t-PSA concentrations
between patients with organ-confined prostate
cancer and patients with benign prostatichyperplasia. Conversely, approximately 25% of
patients with prostate cancer show no elevation of
serum t-PSA and must be diagnosed by other
methods, e.g. digital rectal examination. Increased
serum PSA concentrations and/or abnormal digital
rectal examination can only raise the suspicion of
prostate cancer..
REFERENCES
1.Stenman UH, Hakama M, Knekt P, Aromaa A, TeppoL, Leinonen J: Serum concentrations of prostate
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specific antigen and its complex with alpha1-
antichymotrypsin before diagnosis of prostate
cancer. Lancet 344: 1594-1598, 1994.2.Lilja H, Christensson A, Dahlen U, Matikainen MT,
Nilsson O, Pettersson K, et al: Prostate-specific
antigen in serum occurs predominantly in complex
with alpha-1-antichymotrypsin. Clin Chem 37: 1618-1625, 1991.
3.Christensson A, Bjrk T, Nilsson O, Dahlen U,Matikainen M, Cockett ATK, et al: Serum prostate
specific antigen complexed to alpha 1-
antichymotrypsin as an indicator of prostate cancer.
J Urol 150: 100-105, 1993.
4.Wirth MP, Frohmller HGW: Prostate specific antigenand prostate acid phosphatase in the detection of
early prostate cancer and the prediction of regional
lymph node metastases. Eur Urol 22: 27-32, 1992.
8/7/2019 Tumour markers in prostate cancer
12/26
5.Kontturi M: Is acid phosphatase (PAP) still justifiedin the management of prostatic cancer? Acta
Oncol 30: 169-170, 1991.6.Stamey TA, Freiha FS, McNeal JE, Redwine EA,
Whittemore AS, Schmid HP: Localized prostate
cancer. Relationship of tumour volume to clinical
significance for treatment of prostate cancer.Cancer 71 Suppl. 3: 933-938, 1993.
7.7 Selley S, Donovan J, Faulkner A, Coast J, Gillatt D:Diagnosis, management and screening of early
localised prostate cancer. Health Technol Assess 1:
No. 2, 1997.
8.Australian Health Technology Advisory Committee:Prostate cancer screening. Canberra, Australian
Health Technology Advisory Committee, 1996.
9.Schrder FH, Boyle P: Screening for prostate cancer- necessity or nonsense? Eur J Cancer 29A: 656-661,
1993.
8/7/2019 Tumour markers in prostate cancer
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10.Babaian RJ, Miyashita H, Evans RB, vonEschenbach AC, Ramirez EI: Early detection program
for prostate cancer: results and identification ofhigh-risk patient population. Urology 37: 193-197,
1991.
11.Catalona WJ, Richie JP, Ahmann FR, Hudson MA,Scardino PT, Flanigan RC, et al: Comparison ofdigital rectal examination and serum prostate
specific antigen in the early detection of prostate
cancer: results of a multicenter clinical trial of 6,630
men. J Urol 151: 1283-1290, 1994.
12.Dorr VJ, Williamson, Stephens RL: An evaluationof prostate -specific antigen as a screening test for
prostate cancer. Arch Intern Med 153: 2529-2537,
1993.
13.Schrder FH, Bangma CH: The Europeanrandomized study of screening for prostate cancer
(ERSPC). Brit J Urol 79 Suppl.: 68-71, 1997.
8/7/2019 Tumour markers in prostate cancer
14/26
14.Veneziano S, Pavlica P, Querz R, Nanni G,Lalanne MG, Vecchi F: Correlation between prostate-
specific antigen and prostate volume evaluated bytransrectal ultrasonography: usefulness in diagnosis
of prostate cancer. Eur Urol 18: 112-116, 1990.
15.Babaian RJ, Miyashita H, Evans RB, Ramirez EI:The distribution of prostate specific antigen in menwithout clinical or pathological evidence of prostate
cancer: relationship to gland volume and age. J
Urol 147: 837-840, 1992.
16.Benson MC, Whang IS, Olsson CA, McMahon DJ,Cooner WH: The use of prostate specific antigen
density to enhance the predictive value of
intermediate levels of serum prostate specific
antigen. J Urol 147: 817-821, 1992.
17.Oesterling JE, Jacobsen SJ, Chute CG, Guess HA,Girman CJ, Panser LA, et al: Serum prostate-specific
antigen in a community-based population of healthy
8/7/2019 Tumour markers in prostate cancer
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men - Establishment of age-specific reference
ranges. JAMA 270: 860-864, 1993.
18.Paul R, Breul J, Hartung R: Prostate-specificantigen density and age-specific prostate-specific
antigen values: the solution of prostate cancer
screening? Eur Urol 27: 286-291, 1995.
19.Etzioni R, Shen Y, Petteway JC, Brawer MK: Age-specific prostate-specific antigen: a reassessment.
Prostate Suppl. 7: 70-77, 1996.
20.Carter BC, Pearson JD, Metter EJ, Brant LJ, ChanDW, Andres R et al: Longitudinal evaluation of
prostate-specific antigen levels in men with and
without prostate disease. JAMA 267: 2215-2220,
1992.
21.Gann PH, Hennekens CH, Stampfer MJ: Aprospective evaluation of plasma prostate-specific
antigen for detection of prostatic cancer. JAMA 273:
289-294, 1995.
8/7/2019 Tumour markers in prostate cancer
16/26
22.Schmid HP: Prostate specific antigen doubling timein diagnosis and follow-up of patients with prostate
cancer. Tumour Marker Update 8: 71-77, 1996.23.Catalona WJ, Smith DS, Wolfert RL, Wang TJ,
Rittenhouse HG, Ratliff TL, et al: Evaluation of
percentage of free serum prostate-specific antigen
to improve specificity of prostate cancer screening.JAMA 274: 1214-1220, 1995.
24.Catalona WJ, Partin AW, Slawin KM, Brawer MK,Flanigan RC, Patel A, et al: Use of the percentage of
free prostate-specific antigen to enhance
differentiation of prostate cancer from benign
prostatic disease. JAMA 279: 1542-1547, 1998.
25.Stenman UH, Leinonen J, Alfthan H, Rannikko S,Tuhkanen K, Alfthan O: A complex between
prostate-specific antigen and alpha 1-
antichymotrypsin is the major form of prostate-
specific antigen in serum of patients with prostatic
8/7/2019 Tumour markers in prostate cancer
17/26
cancer: assay of the complex improves clinical
sensitivity for cancer. Cancer Res 51: 222-226,
1991.
Tumour markers in prostate cancer
The most useful tumour marker for prostate cancer
at present is prostate-specific antigen (PSA). PSA is
a glycoprotein that is almost exclusively produced in
the prostate. The major forms that presently can be
determined in human serum are the uncomplexed,
free form (f-PSA, MW ~33 kD) and a complex of f-
PSA with E1-antichymotrypsin (MW ~100 kD). Bothforms represent the main fraction of total PSA (t-
PSA) that can currently be identified in human
serum (1-3).
The determination of prostatic acid phosphatase(PAP) does not add clinically useful information to
8/7/2019 Tumour markers in prostate cancer
18/26
PSA measurement, and is therefore not
recommended (4,5).
Screening and diagnosis
The use of PSA for the detection of prostate cancer
leads to an earlier diagnosis and probably more
curable stages of the disease are detected. On the
other hand, knowledge of the natural history of early
lesions suggests that indiscriminate use of PSA will
lead to overdiagnosis and overtreatment in some
cases (6). Information on the effectiveness of
treatment is currently unavailable, and no evidence
exists that early diagnosis and treatment will lead to
an improvement of disease-related and overall
mortality (7,8). Despite these uncertainties it is
proposed that use of the PSA test should not bewithheld from symptomatic men and those who wish
to be examined for the presence of prostate cancer.
8/7/2019 Tumour markers in prostate cancer
19/26
Application to the general population should depend,
however, on the results of prospective randomized
studies showing that early detection and treatmentcan decrease prostate cancer mortality (9). Since
the positive predictive value (number of positive
tests in patients with the disease divided by the total
number of tests performed) of PSA in screeningpopulations is disturbingly low (~30%) it is
necessary to enhance the specificity of the tumour
marker (10-13).
REFERENCES
1.Stenman UH, Hakama M, Knekt P, Aromaa A, TeppoL, Leinonen J: Serum concentrations of prostate
specific antigen and its complex with alpha1-
antichymotrypsin before diagnosis of prostate
cancer. Lancet 344: 1594-1598, 1994.
8/7/2019 Tumour markers in prostate cancer
20/26
2.Lilja H, Christensson A, Dahlen U, Matikainen MT,Nilsson O, Pettersson K, et al: Prostate-specific
antigen in serum occurs predominantly in complexwith alpha-1-antichymotrypsin. Clin Chem 37: 1618-
1625, 1991.
3.Christensson A, Bjrk T, Nilsson O, Dahlen U,Matikainen M, Cockett ATK, et al: Serum prostatespecific antigen complexed to alpha 1-
antichymotrypsin as an indicator of prostate cancer.
J Urol 150: 100-105, 1993.
4.Wirth MP, Frohmller HGW: Prostate specific antigenand prostate acid phosphatase in the detection of
early prostate cancer and the prediction of regional
lymph node metastases. Eur Urol 22: 27-32, 1992.
5.Kontturi M: Is acid phosphatase (PAP) still justifiedin the management of prostatic cancer? Acta
Oncol 30: 169-170, 1991.
8/7/2019 Tumour markers in prostate cancer
21/26
6.Stamey TA, Freiha FS, McNeal JE, Redwine EA,Whittemore AS, Schmid HP: Localized prostate
cancer. Relationship of tumour volume to clinicalsignificance for treatment of prostate cancer.
Cancer 71 Suppl. 3: 933-938, 1993.
7.7 Selley S, Donovan J, Faulkner A, Coast J, Gillatt D:Diagnosis, management and screening of earlylocalised prostate cancer. Health Technol Assess 1:
No. 2, 1997.
8.Australian Health Technology Advisory Committee:Prostate cancer screening. Canberra, Australian
Health Technology Advisory Committee, 1996.
9.Schrder FH, Boyle P: Screening for prostate cancer- necessity or nonsense? Eur J Cancer 29A: 656-661,
1993.
10. Babaian RJ, Miyashita H, Evans RB, vonEschenbach AC, Ramirez EI: Early detection program
for prostate cancer: results and identification of
8/7/2019 Tumour markers in prostate cancer
22/26
high-risk patient population. Urology 37: 193-197,
1991.
11. Catalona WJ, Richie JP, Ahmann FR, Hudson MA,Scardino PT, Flanigan RC, et al: Comparison of
digital rectal examination and serum prostate
specific antigen in the early detection of prostate
cancer: results of a multicenter clinical trial of 6,630men. J Urol 151: 1283-1290, 1994.
12. Dorr VJ, Williamson, Stephens RL: An evaluationof prostate -specific antigen as a screening test for
prostate cancer. Arch Intern Med 153: 2529-2537,
1993.
13. Schrder FH, Bangma CH: The Europeanrandomized study of screening for prostate cancer
(ERSPC). Brit J Urol 79 Suppl.: 68-71, 1997.
14. Veneziano S, Pavlica P, Querz R, Nanni G,Lalanne MG, Vecchi F: Correlation between prostate-
specific antigen and prostate volume evaluated by
8/7/2019 Tumour markers in prostate cancer
23/26
transrectal ultrasonography: usefulness in diagnosis
of prostate cancer. Eur Urol 18: 112-116, 1990.
15. Babaian RJ, Miyashita H, Evans RB, Ramirez EI:The distribution of prostate specific antigen in men
without clinical or pathological evidence of prostate
cancer: relationship to gland volume and age. J
Urol 147: 837-840, 1992.16. Benson MC, Whang IS, Olsson CA, McMahon DJ,
Cooner WH: The use of prostate specific antigen
density to enhance the predictive value of
intermediate levels of serum prostate specific
antigen. J Urol 147: 817-821, 1992.
17. Oesterling JE, Jacobsen SJ, Chute CG, Guess HA,Girman CJ, Panser LA, et al: Serum prostate-specific
antigen in a community-based population of healthy
men - Establishment of age-specific reference
ranges. JAMA 270: 860-864, 1993.
8/7/2019 Tumour markers in prostate cancer
24/26
18. Paul R, Breul J, Hartung R: Prostate-specificantigen density and age-specific prostate-specific
antigen values: the solution of prostate cancerscreening? Eur Urol 27: 286-291, 1995.
19. Etzioni R, Shen Y, Petteway JC, Brawer MK: Age-specific prostate-specific antigen: a reassessment.
Prostate Suppl. 7: 70-77, 1996.20. Carter BC, Pearson JD, Metter EJ, Brant LJ, Chan
DW, Andres R et al: Longitudinal evaluation of
prostate-specific antigen levels in men with and
without prostate disease. JAMA 267: 2215-2220,
1992.
21. Gann PH, Hennekens CH, Stampfer MJ: Aprospective evaluation of plasma prostate-specific
antigen for detection of prostatic cancer. JAMA 273:
289-294, 1995.
22. Schmid HP: Prostate specific antigen doublingtime in diagnosis and follow-up of patients with
8/7/2019 Tumour markers in prostate cancer
25/26
prostate cancer. Tumour Marker Update 8: 71-77,
1996.
23. Catalona WJ, Smith DS, Wolfert RL, Wang TJ,Rittenhouse HG, Ratliff TL, et al: Evaluation of
percentage of free serum prostate-specific antigen
to improve specificity of prostate cancer screening.
JAMA 274: 1214-1220, 1995.24. Catalona WJ, Partin AW, Slawin KM, Brawer MK,
Flanigan RC, Patel A, et al: Use of the percentage of
free prostate-specific antigen to enhance
differentiation of prostate cancer from benign
prostatic disease. JAMA 279: 1542-1547, 1998.
25. ranges for prostate-specific antigen in blackmen. N Engl J Med 335: 304-310, 1996.
26. Collins GN, Martin PJ, Wynn-Davies A, BroomanPJ, O'Reilly PH: The effect of digital rectal
examination, flexible cystoscopy and prostatic biopsy
on free and total prostate specific antigen, and the
8/7/2019 Tumour markers in prostate cancer
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free-to-total prostate specific antigen ratio in clinical
practice. J Urol 157: 1744-1747, 1997.
Author has been Senior
Resident in PGIMER,
Chandigarh .He is now working
as Associate Professor in the
department of BIOCHEMISTRY
Baba Farid University of Health
Sciences, Faridkot Punjab India
for the last 13 Years.
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