Efficacy of lower cut off value of serum prostate specific antigen in diagnosis of prostate cancer

Indications of prostate biopsy are high serum prostate specific antigen (PSA) value and or abnormal digital rectal examination (DRE) findings. Although serum PSA value of 4 ng/ml is the most commonly used threshold for recommending prostate biopsy, significant proportion of men harbor prostate cancer even when their serum PSA values are less than 4.0 ng/ml. Therefore present study was designed to determine the performance status of serum PSA in lower cut-off values. This hospital based prospective study was conducted in the Department of Urology of Bangabandhu Sheikh Mujib Medical University (BSMMU) and Comfort Nursing Home Pvt. Ltd, Dhaka from July 2009 to October 2010. Two hundred six male patients aged over 50 years having lower urinary tract symptoms (LUTS) and serum PSA more than 2.5 ng/ml were prepared for prostate biopsy. Trans rectal ultrasound (TRUS) guided biopsy was done. The test statistics used to analyze the data were descriptive statistics, sensitivity, specificity, positive and negative predictive value, ROC curve. For all analytical tests, the level of significance was set at 0.05 and p<0.05 was considered significant. In 2.5-4 serum PSA range, 28.26% (13 out of 46) of all malignancy were found, which would be missed if we take cut off value 4. At 2.5 PSA cut-off, Sensitivity 91.3%, Specificity 14.37%, PPV 23.46%, NPV 85.18%, Efficacy 31.55%. At 4 PSA cut-off value, Sensitivity 71.73%, Specificity 46.25%, PPV 27.73%, NPV 85.05%, Efficacy 51.94%. So it can be concluded that, for early diagnosis of prostate cancer cut-off value of serum PSA of 2.5 ng/ml can be recommended as an indication for prostate biopsy.


Introduction
Prostate cancer is the most common cancer in men and the second leading cause of male cancer deaths in the United States.The estimated lifetime risk of disease is 17.6% for whites and 20.6% for African Americans, with a lifetime risk of death of 2.8% and 4.7% respectively 1 .Worldwide, prostate cancer is the fourth most common cancer in men with incidence and mortality rates that vary markedly among and within different countries 2 .
Unfortunately, the disease is uniformly fatal once the tumor metastasizes outside the gland.But if diagnosed early, surgery or radiotherapy provides excellent results with regard to local disease control and the prospect for long-term, disease-free survival.In the absence of effective treatment options for advanced prostate cancer, intensive efforts to detect low stage, curable cancers may help to improve prostate cancer-specific survival 3 .
In 1979, Wang and his colleagues at Roseville Park isolated prostate-specific antigen (PSA) from prostate tissue 4 .PSA appears to be the best overall serum marker for prostate cancer.The widespread use of serum Prostate Specific Antigen testing for early prostate cancer detection has increased proportion of early stage cancers detected and partially responsible for the recent decrease in prostate cancer mortality rates in the United States .A PSA cutoff of 4ng/ml is generally used for recommending a biopsy 5 .
According to a study, cancer is detected in initial or early follow-up biopsies in more than one third of man with PSA levels greater than 4 ng/ml 6 .However, about 20% of detectable cancers occur in men with PSA values below this cutoff, and the cancer has extended beyond the prostate in one third of men with PSA levels between 4 and 10 ng/ml and in more than half with PSA levels greater than 10 ng/ml 7 .Therefore, the use of lower PSA cutoffs may detect prostate cancer more frequently in its curable stages.
In one study surgical specimen of radical prostatectomy revealed organ confined disease in 88% for 2.6 to 4 ng/ml PSA range versus 63% for 4.0 to 10 ng/ml PSA range (p<.01) 8 .Screening studies have suggested that a 2.5 ng/ml PSA cutoff detects more potentially curable cancers without over detecting harmless ones 7 .Prostate cancer is not uncommon in Bangladesh.Therefore, present study is designed to determine the sensitivity, specificity, positive and negative predictive value of PSA for diagnosis of prostate cancer in lower cut-off values.

Materials and Methods
This hospital based prospective study was conducted in the Department of Urology of Bangabandhu Sheikh Mujib Medical University (BSMMU) and Comfort Nursing Home Pvt.Ltd, Dhaka from July 2009 to October 2010 to determine the performance status of serum PSA in lower cut-off values.All male patients aged over 50 years having lower urinary tract symptoms (LUTS) attending to urology OPD were evaluated by history, clinical examination and necessary investigations to identify the potential candidates for prostate biopsy.Three hundred one patients were interviewed, 252(83.72%)were selected according to selection criteria.Among them 206 patients having serum PSA more than 2.5 ng/ml were prepared for prostate biopsy after receiving consent.One fifty patients were taken from BSMMU and 56 patients were from Comfort Nursing Home.Patients with Serum PSA level <2.5 ng/ml, patient with bleeding disorder, anorectal pathology, active UTI or prostatitis were excluded from the study.Biopsy was done in left lateral position under the guidance of trans rectal ultrasonogram (TRUS) using biopty gun.
Data were processed and analyzed using SPSS (Statistical Package for Social Sciences) software.
The statistical tests used to analyze the data were descriptive statistics, Chi-square ( 2 ) test, sensitivity, specificity, positive and negative predictive value, ROC curve.For all analytical tests, the level of significance was set at 0.05 and p < 0.05 was considered significant.
In 2.5-4 serum PSA range, 28.26 % (13 out of 46) of all malignancies were found, which would be missed if we take cut-off value 4 (Table II).
Sensitivity, specificity, positive and negative predictive value and efficacy at different PSA cut off was as follows-(Table III).IV).

Discussion
The use of PSA as a screening test been directed towards the early detection of prostate cancer and level of 4 ng/ml was proposed as the upper limit of normal range 9 .But it has been seen that a considerable proportion of prostate cancer is found at serum PSA level <4 ng/ml.
In our series, In 2.5-2.99PSA range, 14.81% cases were malignant; 3.0-3.49range, 17.39% cases were malignant, 3.5-3.99range, 13.51% cases were malignant and >3.99 range, 27.73% cases were malignant.Early invasive investigations may result in many men undergoing unnecessary biopsy with a possible increase in the diagnosis of clinically insignificant cancers, whereas postponing prostate biopsy may result in a missed opportunity to identify early, perhaps lifesaving treatment in patients with aggressive cancers.In a large study from Washington University, biopsy in 36% of men in a screening population with PSA 2.5 to 4.0 ng/ ml revealed cancer in 22 % 10 .As is readily apparent, these findings are similar to those found in men with PSA between 4.1 and 10 ng/ml.Catalona et al (1999) reported that 83% of patients with PSA between 2.6 and 4.0 ng/ml who underwent prostatectomy had significant disease defined as greater that 0.5 cm tumor volume 5 .Whether lowering the PSA cutoff value to 2.5 ng/ ml will increase the disease specific survival rate remains to be determined.
In our study, in 2.5-4 serum PSA range, 28.26 % of all malignancies were found, which would be missed if we take cut off value 4. Out of 87 patients in this group, 13(14.94%)cases were found malignant.We found that 38.5% of these tumors are poorly differentiated having >7 Gleason's score. In ROC curve was made.(Fig 1) With PSA cut-off value 2.5, AUC is 0.528 (p=0.557); with PSA cutoff value 3.5, AUC is 0.544 (p value 0.360); with PSA cut-off value 4, AUC is 0.590 (p=0.063)(Fig 1).

Fig 1 :
Fig 1: ROC Curve using different PSA cut off values It was seen that 38.5% of prostate cancer diagnosed in 2.5-4 PSA range had Gleason's score 7-10, which were high grade cancer (TableIV).

Table - I
: Percentage of malignancy in various PSA range

Table -
III: Efficacy of PSA at different cut off value 18tients and health care professionals must be reeducated that there is a continuum of risk and no clearly defined PSA cut point at which to recommend biopsy 17 .It will be the patient, in concert with his health care professional, who will ultimately have to weigh the sensitivity-specificity tradeoffs in combination with the uncertain natural history of the disease to determine whether further evaluation with a prostate biopsy is appropriate18.Conclusion:Usually, serum PSA 4 ng/ml is taken as cut off value as an indication of prostatic biopsy to diagnose prostate cancer.But about 25% of prostate cancer is missed at this PSA cut off value.For early diagnosis of prostate cancer cut off value of serum PSA of 2.5 ng/ml can be recommended as an indication for prostate biopsy.This threshold has been shown in many studies to increase the rate of cancer detection at a stage when cure is possible without materially increasing the proportion of "harmless" prostate cancer detected.