Introduction

Prostate cancer is one of most important health problems suffered by the male population. It’s considered as the second most common cause of cancer-related death after lung cancer. Prostate cancer is the fifth most common cancer in the world (1). Prostate specific antigen (PSA) is a widely used marker for prostate cancer diagnosis and monitoring. PSA is a prostate-specific marker and not cancer-specific, and so any prostate disease including infection and benign enlargement, as well as cancer can cause PSA levels to rise (2). PSA level of 4.0 ng/ml was accepted as the threshold value for the diagnosis of prostate cancer at the beginning of 1990. This value is considered as the border for prostate biopsy indication in men with normal digital rectal examination (DRE) (3,4). However, prostate cancer was detected in %5-20 of patients with PSA level of 4.0 ng/ml or less (5,6). Prostate cancer was detected in %5-30 of patients with PSA level of 2.0 ng/ml or less. Nowadays, there is no clear PSA value for prostate biopsy in guidelines. DRE, transrectal ultrasonography (TRUS) and risk assessment is recommended for biopsy with PSA (7).

In this study, we aimed to investigate the significance of DRE for the decision of biopsy in patients with PSA level of ≤4 ng/ml.

Materials and Methods

We retrospectively analyzed the data of 3781 patients who underwent transrectal prostate biopsy between 2009 and 2014, due to suspicion of prostate cancer. A total of 287 patients with abnormal DRE and PSA level of ≤4 ng/ml were enrolled in the study. Demographic parameters, DRE findings, PSA value, biopsy results and gleason score were noted for all patients. We have categorized the patients into different groups according to their PSA values (in ng/ml: 0-0.9, 1-1.9, 2-2.9, 3-4), clinical stage (in stage: II (T1cN0M0, T2N0M0), III (T3N0M0), and IV (N1 or M1)) and Gleason scores (in GS: 2-6, 7, 8-10). Patient data were collected from computer-based patient record system. Patients who used dutasteride were excluded from the study.

Serum PSA levels were measured using Beckman Hybritech Prostate Specific Antigen (PSA) Kit. Palpable induration, nodularity, irregularity and stifness was accepted as abnormal DRE findings. Prostate volume was measured by TRUS using formula (height x width x length x 0.52). TRUS-guided systematic 12-core biopsy was performed, and if TRUS revealed any abnormal findings, we were performed additional biopsies from abnormal area. All biopsies were performed using a 6.5 MHz transrectal ultrasound-guided biopsy probes and 18-gauge needle with automatic biopsy gun. Patients were treated with 500 mg ciprofloxacin twice daily before the biopsy and were recommended to continue for at least 3 days after the biopsy. Rectal enema was administered before biopsy. Transrectal injection was performed with %2, 20 ml lidocaine for local anesthesia. Statistical analyses were performed with SPPSS 17.0. Statistical comparisons were performed using independent sample t test and Chi-square test. Statistical significance was set at a p value of <0.05.

Results

Clinical characteristics of 407 patients who underwent prostate biopsy for PSA less than 4 ng/ml and/or DRE suspicious for cancer, according to PSA value, are shown in Table 1. 287 patients had both abnormal DRE findings and a PSA level of ≤4 ng/ml. A total of 99 prostate cancers (24.3%) were detected with prostate biopsy. The cancer detection rate was 8.6% (2 of 23) and 7.1% (1 of 14) in patients with PSA value of 0-0.9 ng/ml and 1.0-1.9 ng/ml, respectively. However, the detection rate of prostate cancer was comparatively high at 19.5% (17 of 87) and 27.9% (79 of 283) in patients with PSA value of 2.0-2.9 ng/ml and 3.0-4.0 ng/ml, respectively. 78.8% of patients with prostate cancer in biopsy had positive and 21.2% had negative DRE findings. The proportion of clinical Stage II (T1cN0M0, T2N0M0), III (T3N0M0), and IV (N1 or M1) was 85.8%, 12.1%, and 2.1%, respectively. Clinically insignificant prostate cancer was detected in two cases with 5% or less of one biopsy core. In two patients with PSA value of 0.48 ng/ml and 0.17 ng/ml, squamous cell carcinoma and undifferentiated carcinoma of prostate was detected, respectively. Distant metastasis was determined in both of these patients by bone scintigraphy. These patients were accepted as stage 4 disease.

Detection rates of prostate cancer relative to positive digital rectal examination at varying prostate specific antigen levels are shown in Table 2. In patients with abnormal DRE findings, the detection rate was low in patients with PSA level of <2 ng/ml. The detection rate was 11.8%(2 of 17), 8.3%(1 of 12), 23.3%(14 of 60) and 30.8% (61 of 198) in men with PSA value of 0-0.9 ng/ml, 1.0-1.9 ng/ml, 2.0-2.9 ng/ml and 3.0-4.0 ng/ml, respectively.
Statistical analysis of abnormal DRE in the detection of prostate cancer at varying prostate specific antigen levels are shown in Table 3. Overall, an abnormal DRE had 27.1% positive predictive value (PPV), 82.5% negative predictive value (NPV), 78.7% sensitivity and 32.1% specificity.

Discussion

Prostate cancer patients are usually asymptomatic unless it is very advanced. Elevation of serum PSA or detection of abnormal DRE findings suggests the possibility of prostate cancer. Prostate needle biopsy is the most commonly used diagnostic method for definitive and differential diagnosis of these patients. Nevertheless, threshold value of PSA for prostate biopsy is still controversial (8). For less than 20% of patients, DRE is the only indicator for prostate biopsy. Among patients with suspicious DRE and low PSA (<2 ng/ml), the mean volume of tumors and Gleason score were less than 0.5 cc and 6, respectively (9). DRE is an inexpensive and simple test, but sensitivity and specificity is relatively low (10). The PPV for DRE ranges from 21% to 53% depending on the degree of suspicion for cancer and whether the population studied are referred or screened (11,12,13). DRE and serum PSA are useful first line tests for assessing the risk of prostate cancer (13,14,15).

Some studies on the importance of DRE in patients with PSA levels of 4.0 ng/ml or less have been done. In USA, the detection rate of prostate cancer in patients with a PSA level of 4.0 ng/ml or less and abnormal findings on DRE were found between 10% and 26% (13,16,17). In our study, the detection rate of prostate cancer was 24.3% in parallel to previous studies. Catalona and colleagues reported cancer detection rate was 22% on 363 men who underwent prostate biopsy with PSA levels between 2.6 and 4.0 ng/ml. 81% of those prostate cancer patients undergoing surgery demonstrated organ-confined disease. Relatively few cancers (17%) were clinically insignificant at the time of surgery (18).

Previous studies have demonstrated that the proportion of patients with a Gleason score of 8 to 10 is between 3.3% and 10.8% in white Americans and 18.4% in black Americans with the same findings on DRE and the same PSA level (16,17). In a previous study, the rate of patients with a Gleason score of 8 to 10 on the radical prostatectomy specimen was reported 0% in Dutchmen with abnormal DRE and/or TRUS and PSA level of less than 4.0 ng/ml (19). In our study, %8.1 (8 of 99) of patients had a gleason score between 8 and 10 on biopsy which was similar previous studies. In the present study only one patient had a gleason score between 8 and 10 on radical prostatectomy specimen.

The rate of patients with stage II disease was 87.3%, 88.2%, and 100% in men with prostate cancer and PSA levels of 3.0-4.0 ng/ml, 2-2.9 ng/ml and 1-1.9 ng/ml, respectively. In our study, the rate of stage II disease in patients with PSA level between 2.0 and 4.0 ng/ml was significantly lower than patients with PSA levels between 1.0 and 1.9 ng/ml (p<0.05). Although this result is statistically significant, it is not correct to evaluate due to the lack of patients with psa level of 1.0-1.9 ng/ml. Stage IV non-adenocarcinoma prostate cancer was observed in two patients with PSA level of less than 0.9 ng/ml. In previous studies organ-confined disease was between 84% and 87.9% in patients who underwent radical prostatectomy with PSA levels of 4.0 ng/ml or less (7,8,9,10)

In some studies, the detection rate for men with PSA levels of 1.0 to 1.9 ng/ml, 2.0 to 2.9 ng/ml, and 3.0 to 3.9 ng/ml was 8.6% to 13.5%, 13.4% to 27.2%, and 25.4% to 28.7%, respectively. Previous studies have demonstrated that accuracy of the DRE in patients with PSA levels of 4.0 ng/ml or less increased with an increase in PSA levels (16,17,19). In the present study prostate cancer detection rate in patients with a PSA level of 0 to 0.9 ng/ml, 1.0 to 1.9 ng/ml and 2.0 to 4.0 ng/ml were 8.6%, 7.1% and 25.9%, respectively. These rates were similar with previous studies. In our study ,the positive predictive value of abnormal DRE findings in patients with PSA levels of 1.0 ng/mL or less was low at 11.8%; it was 8.0% in other studies (13,16). Because of the PPV of abnormal DRE findings in patients with a PSA level of less than 2.0 ng/ml is very low and NPV of abnormal DRE findings is very high, we do not recommend routine biopsy in men with a PSA level of less than 2.0 ng/ml and without marked abnormal DRE findings.

It is not clear whether to perform biopsy in men with first PSA levels between 2.0 and 4.0 ng/ml immediately. We think that patient age is the most important points to consider in the decision to perform prostate biopsy to detect prostate cancer. Patients with PSA levels between 2.0 to 4.0 ng/ml without abnormal DRE findings should perform prostate biopsy at least once if their PSA level is higher than their age reference range.

Conclusion

DRE, PSA and patient age are important parameter and guides clinicians in the decision of biopsy and management of patients. Because the detection rate of prostate cancer is high in patients level between 2.0-4.0 ng/ml, even though normal digital rectal examination, prostate biopsy should be performed. However prostate biopsy should not be performed patients with normal DRE findings and PSA levels of less than 2.0 ng/ml.

Conflict of interest: The authors reported no conflict of interest related to this article.