prostate - specific antigen ( psa ) measurement in patients with serum psa level above 4.0 ng / ml has a sensitivity of about 20% , and the specificity of psa measurements is approximately 60% to 70% at this cut - off ( 1 ) . if patients with psa levels below 10 ng / ml were submitted to prostate biopsy , 2040% would be diagnosed with prostate cancer and 6080% should undergo unnecessary biopsy without detecting prostate cancer ( 2 ) .
benign prostatic hyperplasia , urethral or prostatic trauma , and prostatitis , as well as prostate cancer , can all be associated with elevated serum psa levels .
ejaculation and digital rectal examinations have been reported to increase psa levels but studies have shown the effects to be variable or insignificant ( 3 ) .
these non - malignant conditions which were associated with elevation of a serum psa would decrease the accuracy of a serum psa . to improve low sensitivity of psa , age - adjusted psa , psa density ( psad ) , psa velocity ( psav ) , or percentage of free psa (
% free - psa ) has been introduced and used ( 4 - 8 ) . in the last two decades , individual fluctuation in serial psa measurements has been reported to characterize the normal biological variability in psa among men without prostate cancer ( 9 - 13 ) .
the aims of this study were to investigate whether psa fluctuation correlates with a prostate cancer and to assess whether psa fluctuation could be used for diagnosis of a prostate cancer .
this was a retrospective cohort study in the department of urology of chonnam national university hospital ( gwangju , korea ) between january , 2012 and march , 2013 .
this study included 229 patients who were submitted to a transrectal ultrasonography ( trus ) guided prostate biopsy ( 177 in non - cancer group , 52 in prostate cancer group ) .
trus - guided prostate biopsy was performed in at least 8 cores or more of tissue targeting the peripheral zone at the apex , mid gland , and base on each side of the prostate .
enrolled patients were provided twice psa measurements within 6 months ( baseline psa , psa1 ; secondary psa , psa2 ) , and psa2 was measured at the day before prostate biopsy .
patients with urinary tract infection and who were receiving a 5-alpha reductase inhibitor were excluded from the study .
the research attained ethical approval from the institutional review board of connam national university hospital ( irb no .
210 - 05 - 082 ) . the recommendations of the declaration of helsinki for biomedical research involving human subjects were followed
psa fluctuation ( % /mo ) was defined as a change rate of psa ( ( psa2-psa1)/psa1 ) per a month .
psad ( ng / ml / g ) was defined as a psa2 divided by prostate volume .
prostate volume ( g ) was measured according to the prostate ellipsoid formula , multiplying the largest anteroposterior ( height , h ) , transverse ( width , w ) , and cephalocaudal ( length , l ) prostate diameters by 0.524 ( h  w
an automated immunoassay analyzer ( architect i2000sr , abbott diagnostics , abbott park , il , usa ) was used for all psa measurements , and trus - guided prostate biopsy was recommended for a psa level > 3.0 ng / ml or suspicious digital rectal examination .
receiver operator characteristic ( roc ) curve was used to assess the availability as a differential diagnostic tool and the correlation .
simple linear regression was performed to analyze a correlation between psa fluctuation and other factors such as age , psa , psad , and prostate volume .
this was a retrospective cohort study in the department of urology of chonnam national university hospital ( gwangju , korea ) between january , 2012 and march , 2013 .
this study included 229 patients who were submitted to a transrectal ultrasonography ( trus ) guided prostate biopsy ( 177 in non - cancer group , 52 in prostate cancer group ) .
trus - guided prostate biopsy was performed in at least 8 cores or more of tissue targeting the peripheral zone at the apex , mid gland , and base on each side of the prostate .
enrolled patients were provided twice psa measurements within 6 months ( baseline psa , psa1 ; secondary psa , psa2 ) , and psa2 was measured at the day before prostate biopsy .
patients with urinary tract infection and who were receiving a 5-alpha reductase inhibitor were excluded from the study .
the research attained ethical approval from the institutional review board of connam national university hospital ( irb no .
210 - 05 - 082 ) . the recommendations of the declaration of helsinki for biomedical research involving human subjects were followed
psa fluctuation ( % /mo ) was defined as a change rate of psa ( ( psa2-psa1)/psa1 ) per a month .
psad ( ng / ml / g ) was defined as a psa2 divided by prostate volume .
prostate volume ( g ) was measured according to the prostate ellipsoid formula , multiplying the largest anteroposterior ( height , h ) , transverse ( width , w ) , and cephalocaudal ( length , l ) prostate diameters by 0.524 ( h  w
architect i2000sr , abbott diagnostics , abbott park , il , usa ) was used for all psa measurements , and trus - guided prostate biopsy was recommended for a psa level > 3.0 ng / ml or suspicious digital rectal examination .
roc ) curve was used to assess the availability as a differential diagnostic tool and the correlation .
simple linear regression was performed to analyze a correlation between psa fluctuation and other factors such as age , psa , psad , and prostate volume .
mean psa1 and psa2 levels were 5.93 ng / ml and 4.90 ng / ml .
psa fluctuation ranged from 0.12%/month to 122.6%/month , psad from 0.01 ng / ml / g to 0.58 ng / ml / g , and prostate volume from 8.9 g to 160 g. patients diagnosed with prostate cancer were 52 ( 22.7% ) , and patients with non - cancer were 177 ( 77.3% ) .
patients with non - cancer presented benign prostatic hyperplasia ( 155 , 67.7% ) , chronic prostatitis ( 16 , 7.0% ) , and atypical small acinar proliferation ( 6 , 2.6% ) . 

table 1baseline characteristics of patients.variablesmean ( range)age ( year)66.91 ( 41 - 85)psa1 ( ng / ml)5.93 ( 0.23 - 24.62)psa2 ( ng / ml)4.90 ( 0.20 - 9.96)interval of psa tests ( month)1.93 ( 1 - 6)psa fluctuation ( % /month)17.61 ( 0.12 - 122.60)psad ( ng / ml / g)0.15 ( 0.01 - 0.58)prostate volume ( g)37.61 ( 8.90 - 160)%free - psa ( % ) 20.22 ( 3.79 - 61.50)no . biopsy results ( % )  non - cancer177 ( 77.3 )  prostate cancer52 ( 22.7 ) 
 psa = 
 prostate - specific antigen , 
 psa 
  = baseline psa , 
 psa 
  = 
 secondary psa , 
 psad = 
 psa density , 
 % free - psa = 
 percentage of free psa . 
 

psa = 
 prostate - specific antigen , 
 psa 
  = baseline psa , 
 psa 
  = 
 secondary psa , 
 psad = 
 psa density , 
 % free - psa = 
 percentage of free psa .
psa2 and psad were significantly lower in non - cancer group than prostate cancer group ( 4.682.18 vs 5.611.76 ng / ml , p=0.002 ; 0.1320.796 vs 0.2270.124 ng / ml / g , p<0.001 ) .
psa fluctuation and % free - psa was significantly greater in non - cancer group than prostate cancer group ( 19.9523.34 vs 9.638.57%/month , p=0.004 ; 21.539.74 vs 15.757.96% , p<0.001 ) .
there was significant difference in prostate volume between the two groups ( 40.1219.93 vs 29.0512.05 g , p<0.001 ) ( table-2 ) . 

non - cancer group ( n=177)prostate cancer group ( n=52)p valueage ( year)66.368.4568.787.610.103psa1 ( ng / ml)6.003.755.701.700.300psa2 ( ng / ml)4.682.185.611.760.002interval of psa tests ( month)1.881.192.071.360.330psa fluctuation ( % /month)19.9523.349.638.570.004%free - psa ( % ) 21.539.7415.757.96<0.001psad ( ng / ml / g)0.1320.7960.2270.124<0.001prostate volume ( g)40.1219.9329.0512.05<0.001 
 psa 
 = prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 
  = 
 secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density . 
 

psa 
 = prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 
  = 
 secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density .
psa2 , psad , % free - psa , and psa fluctuation was statistically significant as a differential diagnostic tool . the optimal cut - off
values for detecting prostate cancer of psa and psad were defined as 4.92 ng / ml ( sensitivity , 65.4% ; specificity , 56.5% ; area under curve ( auc ) , 0.64 ; p=0.002 ) and 0.155 ng / ml / g ( sensitivity , 73.1% ; specificity , 71.2% ; auc , 0.762 ; p<0.001 )
. the appropriate cut - off values of % free - psa and psa fluctuation were defined as 17.31% ( sensitivity , 63.3% ; specificity , 63.5% ; auc , 0.688 ; p<0.001 ) and 8.48%/month ( sensitivity , 61.6% ; specificity , 59.6% ; auc , 0.633 ; p=0.004 ) , respectively ( figure-1 ) . 

figure 1receiver operator characteristic curves analyses of secondary prostate - specific antigen ( psa2 ) , prostate - specific antigen density ( psad ) , percentage of free prostate - specific antigen ( % free - psa ) , and prostate - specific antigen ( psa ) fluctuation . the optimal cut - off
values for detecting prostate cancer were defined as 4.92 ng / ml in psa2 ( sensitivity , 65.4% ; specificity , 56.5% ; area under curve ( auc ) , 0.64 ; p=0.002 ) , 0.155 ng / ml / g in psad ( sensitivity , 73.1% ; specificity , 71.2% ; auc , 0.762 ; p<0.001 ) , 17.31% in % free - psa ( sensitivity , 63.3% ; specificity , 63.5% ; auc , 0.688 ; p<0.001 ) , and 8.48 % /month in psa fluctuation ( sensitivity , 61.6% ; specificity , 59.6% ; auc , 0.633 ; p=0.004 ) , respectively . 
 
simple linear regression was performed to analyze a correlation between psa fluctuation and other factors such as age , psa , psad , and prostate volume .
psa1 and psa2 levels were significantly correlated with psa fluctuation in a simple linear regression model ( coefficient b , 3.404 , p<0.001 in psa1 ; coefficient b , -3.978 , p<0.001 in psa2 ) .
age , % free - psa , psad , and prostate volume did not affect on psa fluctuation ( table-3 ) . 

table 3simple linear regression analyses of prostate - specific antigen fluctuation and clinical parameters.variablescoefficient bsep valueage ( year)-0.0590.1700.728psa1 ( ng / ml)3.4040.392<0.001psa2 ( ng / ml)-3.9780.625<0.001%free - psa ( % ) 0.1630.1650.325psad ( ng / ml / g)-20.06116.0290.212prostate volume ( g)-0.0290.0750.696 
 psa = 
 prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 = secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density . 
 

psa = 
 prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 = secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density .
mean psa1 and psa2 levels were 5.93 ng / ml and 4.90 ng / ml .
psa fluctuation ranged from 0.12%/month to 122.6%/month , psad from 0.01 ng / ml / g to 0.58 ng / ml / g , and prostate volume from 8.9 g to 160 g. patients diagnosed with prostate cancer were 52 ( 22.7% ) , and patients with non - cancer were 177 ( 77.3% ) .
patients with non - cancer presented benign prostatic hyperplasia ( 155 , 67.7% ) , chronic prostatitis ( 16 , 7.0% ) , and atypical small acinar proliferation ( 6 , 2.6% ) . 

table 1baseline characteristics of patients.variablesmean ( range)age ( year)66.91 ( 41 - 85)psa1 ( ng / ml)5.93 ( 0.23 - 24.62)psa2 ( ng / ml)4.90 ( 0.20 - 9.96)interval of psa tests ( month)1.93 ( 1 - 6)psa fluctuation ( % /month)17.61 ( 0.12 - 122.60)psad ( ng / ml / g)0.15 ( 0.01 - 0.58)prostate volume ( g)37.61 ( 8.90 - 160)%free - psa ( % ) 20.22 ( 3.79 - 61.50)no . biopsy results ( % )  non - cancer177 ( 77.3 )  prostate cancer52 ( 22.7 ) 
 psa = 
 prostate - specific antigen , 
 psa 
  = baseline psa , 
 psa 
  = 
 secondary psa , 
 psad = 
 psa density , 
 % free - psa = 
 percentage of free psa . 
 

psa = 
 prostate - specific antigen , 
 psa 
  = baseline psa , 
 psa 
  = 
 secondary psa , 
 psad = 
 psa density , 
 % free - psa = 
 percentage of free psa .
psa2 and psad were significantly lower in non - cancer group than prostate cancer group ( 4.682.18 vs 5.611.76 ng / ml , p=0.002 ; 0.1320.796 vs 0.2270.124 ng / ml / g , p<0.001 ) .
psa fluctuation and % free - psa was significantly greater in non - cancer group than prostate cancer group ( 19.9523.34 vs 9.638.57%/month , p=0.004 ; 21.539.74 vs 15.757.96% , p<0.001 ) .
there was significant difference in prostate volume between the two groups ( 40.1219.93 vs 29.0512.05 g , p<0.001 ) ( table-2 ) . 

non - cancer group ( n=177)prostate cancer group ( n=52)p valueage ( year)66.368.4568.787.610.103psa1 ( ng / ml)6.003.755.701.700.300psa2 ( ng / ml)4.682.185.611.760.002interval of psa tests ( month)1.881.192.071.360.330psa fluctuation ( % /month)19.9523.349.638.570.004%free - psa ( % ) 21.539.7415.757.96<0.001psad ( ng / ml / g)0.1320.7960.2270.124<0.001prostate volume ( g)40.1219.9329.0512.05<0.001 
 psa 
 = prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 
  = 
 secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density . 
 
 psa 
 = prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 
  = 
 secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density .
psa2 , psad , % free - psa , and psa fluctuation was statistically significant as a differential diagnostic tool . the optimal cut - off
values for detecting prostate cancer of psa and psad were defined as 4.92 ng / ml ( sensitivity , 65.4% ; specificity , 56.5% ; area under curve ( auc ) , 0.64 ; p=0.002 ) and 0.155 ng / ml / g ( sensitivity , 73.1% ; specificity , 71.2% ; auc , 0.762 ; p<0.001 ) .
the appropriate cut - off values of % free - psa and psa fluctuation were defined as 17.31% ( sensitivity , 63.3% ; specificity , 63.5% ; auc , 0.688 ; p<0.001 ) and 8.48%/month ( sensitivity , 61.6% ; specificity , 59.6% ; auc , 0.633 ; p=0.004 ) , respectively ( figure-1 ) . 

figure 1receiver operator characteristic curves analyses of secondary prostate - specific antigen ( psa2 ) , prostate - specific antigen density ( psad ) , percentage of free prostate - specific antigen ( % free - psa ) , and prostate - specific antigen ( psa ) fluctuation .
the optimal cut - off values for detecting prostate cancer were defined as 4.92 ng / ml in psa2 ( sensitivity , 65.4% ; specificity , 56.5% ; area under curve ( auc ) , 0.64 ; p=0.002 ) , 0.155 ng / ml / g in psad ( sensitivity , 73.1% ; specificity , 71.2% ; auc , 0.762 ; p<0.001 ) , 17.31% in % free - psa ( sensitivity , 63.3% ; specificity , 63.5% ; auc , 0.688 ; p<0.001 ) , and 8.48 % /month in psa fluctuation ( sensitivity , 61.6% ; specificity , 59.6% ; auc , 0.633 ; p=0.004 ) , respectively . 

simple linear regression was performed to analyze a correlation between psa fluctuation and other factors such as age , psa , psad , and prostate volume .
psa1 and psa2 levels were significantly correlated with psa fluctuation in a simple linear regression model ( coefficient b , 3.404 , p<0.001 in psa1 ; coefficient b , -3.978 , p<0.001 in psa2 ) .
age , % free - psa , psad , and prostate volume did not affect on psa fluctuation ( table-3 ) . 

table 3simple linear regression analyses of prostate - specific antigen fluctuation and clinical parameters.variablescoefficient bsep valueage ( year)-0.0590.1700.728psa1 ( ng / ml)3.4040.392<0.001psa2 ( ng / ml)-3.9780.625<0.001%free - psa ( % ) 0.1630.1650.325psad ( ng / ml / g)-20.06116.0290.212prostate volume ( g)-0.0290.0750.696 
 psa = 
 prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 = secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density . 
 
 psa = 
 prostate - specific antigen , 
 psa 
 1 
  = 
 baseline psa , 
  psa 
 2 = secondary psa , 
 % free - psa = 
 percentage of free psa , 
 psad = 
 psa density .
after the recent reports of highly anticipated data from the prostate , lung , colorectal , and ovarian cancer screening trial ( plco ) and the european randomized study of screening for prostate cancer ( erspc ) , the benefit of psa screening remains controversial ( 14 , 15 ) .
twenty - five percent of men with psa levels from 4 to 10 ng / ml have a biopsy - proven prostate cancer , but 75% undergo unnecessary prostate biopsies , potentially leading to anxiety , discomfort , and significant additional health care cost ( 16 ) . to improve the low sensitivity of psa , age - adjusted psa , psad , psav , and % free - psa
have been introduced and used ( 4 - 8 ) . in our study , the sensitivity and specificity of psa was not high ( 65.4% ; 56.5% ; auc , 0.64 ; p=0.002 ) in a roc curve . similarly with previous reports , both psad and % free - psa were the available parameters to improve the low sensitivity of psa ( sensitivity , 73.1% , 63.3% ; specificity , 71.2% , 63.5% ; auc , 0.762 , 0.688 ) .
in addition to psad and % free - psa , we found that psa fluctuation is associated with the presence of a prostate cancer .
although low sensitivity and specificity , psa fluctuation could be valuable by using with other psa indices such as psad and % free - psa . in several studies , biological fluctuations in psa levels have been previously reported to characterize the normal biological variability in psa levels among men without prostate cancer ( 9 - 13 ) .
reported a significant fluctuation between two serum psa measurements obtained within a short - time interval of less than 90 days , and authors suggested not a single psa measurement but repeated psa tests ( 9 ) . in our study ,
mean interval of twice psa measurements was 1.93 months ( approximately 57.9 days ) , and there was no difference in psa1 but significant difference in psa2 between two groups within a more shorter - time interval .
studied to assess the relationship between prostate volume and psa fluctuation , and found that psa fluctuation was not correlated with psa volume but correlated with baseline psa levels ( 11 ) . in our study , psa fluctuation was correlated with baseline psa levels , and not correlated with age , psad , % free - psa , and prostate volume .
thus , we suggest that psa fluctuation could be used for the differential diagnosis regardless with age and prostate volume .
evaluated daily biological variations of psa levels by obtaining 10 serum samples from 24 patients during a 2-week ( 12 ) .
they concluded that the degree of biological fluctuation differs among patients , and the difference between serial psa measurements that is less than 20% to 46% may be due to biological and analytical variation alone .
the reports mentioned above targeted to patients without prostate cancer , and focused on the biologic fluctuation itself .
the hypothesis of our study was that degree of psa fluctuation might differ according to the presence or absence of prostate cancer , and we found the characteristic of psa fluctuation that patients with prostate cancer had a narrow range of fluctuation in serial psa measurements .
in addition , these results are as practically useful as other indices related to psa such as a psad or % free - psa .
it is important to clarify that the psa fluctuation should not be confused with psav as described by carter et al .
psav represent the rate of change of psa over time that optimally requires three consecutive psa measurements over a 2-year period , as described by carter et al .
psa fluctuation is simply a mathematical estimate of the absolute monthly changes in psa ( ng / ml per a month ) between two measurements that can be separated by less than 1 year . in our study , the mechanism of psa fluctuation could not be investigated ; however , psa fluctuation might include the possibility of physiologic changes in serial psa measurements , in contrast with the psav to consider a disease - progression . in our study , when patients with prostate cancer ( n = 52 ) were divided by a gleason score , psa fluctuation was greater in patients with gleason score 6 ( n=22 ) than gleason score 7 ( n=30 ) , although not significantly ( 10.509.45 vs 8.997.97 % /month , p=0.535 ; data are not shown in tables ) .
however , this result might not have sufficient statistical power , due to small sample size .
we carefully suppose that there might be differences in the psa fluctuation between low - risk and high - risk prostate cancer . a study based on larger population is necessary for further conclusive data .
the major limitation is its retrospective design , and thus the present results may be vulnerable to confounding errors and bias .
we enrolled patients that measured two times psa levels within 6 months to minimize the confounding by irregular intervals .
however , we could have concluded about the difference of psa fluctuation between two groups , because psa fluctuation was not correlated with prostate volume in a simple linear regression model . finally , this study may not have had sufficient statistical power , due to the relatively small sample size .
psa fluctuation is significantly greater in patients without cancer than patients with prostate cancer , and is positively correlated with baseline psa level .
thus , clinicians should consider that patients with wide psa fluctuations , although baseline psa levels are high , might have a low risk of diagnosis with prostate cancer , and that serial psa measurements could be an option in patients with an elevated psa level .

 psa = prostate - specific antigen 
 psa 
 1 
  = baseline prostate - specific antigen 
 psa 
 2 
  = secondary prostate - specific antigen 
 psad = prostate - specific antigen density 
 psav = prostate - specific antigen velocity 
 % free - psa = percentage of free prostate - specific antigen 
 trus = transrectal ultrasonography 
 roc = receiver operator characteristic
 objective to investigate whether prostate - specific antigen ( psa ) fluctuation correlates with a prostate cancer and to assess whether psa fluctuation could be used for diagnosis of prostate cancer.materials and methods our study included 229 patients who were performed a prostate biopsy ( non - cancer group , 177 ; prostate cancer group , 52 ) . 
 enrolled patients were provided twice psa tests within 6 months . 
 psa fluctuation ( % /month ) was defined as a change rate of psa per a month . independent t test was used to compare between two groups . 
 receiver operator characteristic curve was used to assess the availability as a differential diagnostic tool and the correlation . 
 simple linear regression was performed to analyze a correlation between psa fluctuation and other factors such as age , psa , psa density , and prostate volume.results there were significant differences in psa , psa density , percentage of free psa , and psa fluctuation between two groups . 
 psa fluctuation was significantly greater in non - cancer group than prostate cancer group ( 19.9523.34%/month vs 9.638.57%/month , p=0.004 ) . 
 the most optimal cut - off value of psa fluctuation was defined as 8.48%/month ( sensitivity , 61.6% ; specificity , 59.6% ; auc , 0.633 ; p=0.004 ) . 
 in a simple linear regression model , only psa level was significantly correlated with psa fluctuation.conclusion patients with wide psa fluctuations , although baseline psa levels are high , might have a low risk of diagnosis with prostate cancer . 
 thus , serial psa measurements could be an option in patients with an elevated psa level . 
INTRODUCTION
MATERIALS AND METHODS
Patients and Study design
Definition and Measurements
Statistical analysis
RESULTS
Baseline Characteristics
Comparison between Non-cancer group and Prostate cancer group
ROC curve analyses of PSA, PSAD, %Free-PSA, and PSA fluctuation
Correlation Analysis between PSA fluctuation and other variables
DISCUSSION
CONCLUSIONS
ABBREVIATIONS