Abstract
Background:
Prostate cancer is the second leading cause of cancer death in men worldwide. There is no national standard for PSA cut-off levels even through the transrectal prostate biopsy procedure causes many serious complications such as bleeding, infection, and sepsis. Therefore, determining cut-off levels for PSA and PSAD is essential to avoid unnecessary biopsies.
Objective:
This study aims to determine the Prostate Specific Antigen (PSA) and Prostate Specific Antigen Density (PSAD) cut-off points in patients with suspected prostate cancer.
Methods:
A retrospective study was conducted from January 2018 until March 2021 in Saiful Anwar General Hospital Malang Indonesia. Inclusion criterias were patients with suspected prostate cancer; > 50 years old; underwent PSA, PSAD, and prostate biopsy. Exclusion criterias were patients refuse to participate in the study and incomplete patient medical record data. Medical records from 53 patients who underwent transrectal ultrasonography (TRUS)-guided prostate biopsy were reviewed. Statistical analysis was performed using Mann-Whitney U, Chi-Square, Fisher’s Exact, and Receiver Operator Characteristic (ROC) curves.
Results and Discussion:
Medical records conducted 53 patients who met inclusion criteria and underwent transrectal ultrasonography (TRUS)-guided prostate biopsy were reviewed. PSA cut off level for prostate biopsy was 19.71 ng/ml with a sensitivity of 69.23% and a specificity of 72.5%. The positive predictive value is 45% and the negative predictive value is 87.87%. PSAD cut off level for prostate biopsy was 0.4113 with a sensitivity of 61.54% and a specificity of 63.16%. The positive predictive value is 36.36% and the negative predictive value is 82.76%.
Conclusion:
Results from this study, the cut off levels of PSA and PSAD in prostate disease patients is higher than the recommended cut off; prostate cancer is the largest malignancy in men worldwide and has a higher incidence in the older age and high serum PSA levels group.
Keywords: cutoff, prostate cancer, PSA, PSAD
1. BACKGROUND
Prostate cancer is the second most diagnosed solid cancer in adult men after non-melanoma skin cancer. Prostate cancer is the second leading cause of cancer death in men worldwide after lung cancer (1). According to the report by International Agency for Research on Cancer in 2018 the prevalence of prostate cancer in Indonesia was 11,361 cases and death due to prostate cancer by 5,007 (2-4).
Most patients with early-stage prostate cancer are asymptomatic, so an elevated PSA is used to detect prostate cancer (5-6). The serum PSA detection rate for prostate cancer reaches a specificity of 91% using a PSA value greater than 4 ng/mL. In comparison, the specificity of digital rectal examination is only about 59%. At cut off level of 4 ng/mL, the PSA value has a sensitivity about 20.5% and a specificity of about 93.6%. If a patient with PSA level below 10 ng/mL undergoes a prostate biopsy, 20.5% will be diagnosed with prostate cancer and 60-80% will have to undergo unnecessary biopsies without detecting prostate cancer. Therefore the best PSA cut-off level for prostate biopsy is debatable (7).
Improving the sensitivity of PSA, age-adjusted PSA, PSAD, PSA velocity (PSAV), or percentage of Free PSA (% Free PSA) have been used. At Saiful Anwar Hospital Malang Indonesia, the patient’s parameter to undergo biopsy is PSA level > 10 ng/ml or PSAD > 0.15 ng/ml for the PSA level 4-10 ng/ml. A study conducted by Mochtar et al in Cipto Mangunkusumo Hospital Jakarta Indonesia found that the optimal PSA cutoff level was 42.7 ng/ml (74% sensitivity, 73% specificity, PPV 85.2%, NPV 57.5%, AUC 0.81%) (7). However, until now there is no standard for PSA cut-off levels in Indonesia and Malang even though the transrectal prostate biopsy procedure causes many serious complications such as bleeding, infection, and sepsis. Therefore, determining cut-off levels for PSA and PSAD is essential to avoid unnecessary biopsies.
2. OBJECTIVE
Based on the preliminary study and the description above, this study aims to determine the PSA and PSAD cut-off points in patients with suspected prostate cancer in Saiful Anwar General Hospital Malang.
3. MATERIAL AND METHODS
A retrospective study was conducted from January 2018 until March 2021. Inclusion criterias in this study were patients with suspected prostate cancer; aged more than 50 years of old; underwent PSA, PSAD, and prostate biopsy. Exclusion criterias in this study were patients refuse to participate in the study and incomplete patient medical record data. The independent variables of the study were: cutoff point of PSA and PSAD. The dependent variables of this study were: patients suspected of prostate cancer. Medical records from 53 patients who underwent transrectal ultrasonography (TRUS)-guided prostate biopsy were reviewed. TRUS-guided prostate biopsies are performed in 12 core of tissue targeting the peripheral zones at the apex, middle, and base of each side of the prostate gland. Other data collection includes clinical symptoms of LUTS, hematuria, urinary retention, age; nodules on the rectal toucher; prostate volume; PSA levels and histopathological findings.
Statistical analysis was performed using descriptive statistical calculations and frequency distributions, Mann-Whitney U, Chi-Square, Fisher’s Exact, and Receiver Operator Characteristic (ROC) curves. Simple linear regression was performed to analyze the association between histopathological findings and other factors such as age, PSA and PSAD levels, prostate volume, and rectal palpation findings. The test results are significant if the p-value is less than 0.05
4. RESULTS
Sample characteristics based on gender, age, PSA, PSAD described on Table 1.
Table 1. Basic characteristics.
| Basic characteristics | Subject | ||
|---|---|---|---|
| n | % | ||
| Age | |||
| 50-59 years old | 12 | 22.64 | |
| 60-69 years old | 33 | 62.24 | |
| 70-79 years old | 6 | 11.32 | |
| 80-89 years old | 2 | 3.77 | |
| Gender | |||
| Man | 53 | 100 | |
| Woman | 0 | 0 | |
| PSA | |||
| <10 ng/ml | 12 | 22.64 | |
| >10 ng/ml | 41 | 77.36 | |
| PSAD | |||
| <0.15 | 7 | 13.73 | |
| ≥0.15 | 44 | 86.27 | |
There was 1 patient (1.89%) with PSA level < 4 ng/ml, 11 patients (20.75%) with PSA level 4-10 ng/ml, and 41 patients (77.36%) with PSA level > 10 ng/ml. At PSA level > 10 ng/ml there were 12 patients (29.27%) diagnosed with prostate cancer. At PSA level of 4-10 ng/ml there was 1 patient (9.09%) diagnosed with prostate cancer. At PSA level < 4 ng/ml there were no patients diagnosed with prostate cancer. The range of PSA level data in patients diagnosed with prostate cancer is 9.76 – 3491 ng/ml while in patients not diagnosed with prostate cancer is 2.49-1222 ng/ml.
Figure 1. PSA ROC Curve. There was found AUC below 0.798 with PSA cut off level 19.71 ng/ml (sensitivity of 69.23% and a specificity of 72.5%).
Table 2. Cross tabulation between PSA and histopathological findings.
| Histopathological findings | Total | ||
|---|---|---|---|
| BPH | Prostat Cancer | ||
| PSA ≥ Cut-off | 11(20,8%) | 9(17,0%) | 20(37,7%) |
| PSA ≤ Cut-off | 29(54,7%) | 4(7,5%) | 33(62,3%) |
| Total | 40(24,5%) | 13(24,5%) | 53(100%) |
PSA cut off level was obtained by Receiver Operating Curve (ROC) curve, the optimal sensitivity and specificity for detecting prostate cancer was the area under the curve (AUC) below 0.798. Then, it was calculated using excel to determine the PSA cut off level for prostate biopsy was 19.71 ng/ml with a sensitivity of 69.23% and a specificity of 72.5%. The positive predictive value of this cut off level is 45% and the negative predictive value of this cut off level is 87.87%.
Figure 2. PSAD ROC Curve. There was found AUC below 0.749 with PSAD cut off level 0.4113 ng/ml (sensitivity of 61.54% and a specificity of 63.16%).
Table 3. Cross tabulation between PSAD and histopathological findings.
| Histopathological findings | Total | ||
|---|---|---|---|
| BPH | Prostat Cancer | ||
| PSAD ≥ Cut-off | 14(27,5%) | 8(15,7%) | 22(43,1%) |
| PSAD ≤ Cut-off | 24(47,1%) | 5(9,8%) | 29(56,9%) |
| Total | 38(74,5%) | 13(25,5%) | 51(100%) |
PSAD cut-off level was obtained with the ROC curve, the optimal sensitivity and specificity for detecting prostate cancer was the AUC below 0.749. Then, it was calculated using excel to determine the PSAD cut off level for prostate biopsy was 0.4113 with a sensitivity of 61.54% and a specificity of 63.16%. The positive predictive value of this cut off level is 36.36% and the negative predictive value of this cut off level is 82.76%.
5. DISCUSSION
This study, only 24.53% of patients had prostate cancer out of 53 patients with prostate disease. This finding follows the research conducted by Siswandi et al. at RS Dr. H. Abdul Moeloek who found more benign prostate enlargement (96.3%) than prostate cancer (3.7%) (8).
According to the American Cancer Society (2017), prostate adenocarcinoma is rarely found in men under 40 years of age, but the risk for prostate cancer increases rapidly after the age of 50 (9). While this study did not find cases with prostate adenocarcinoma patients under 50 years of age of 53 cases. In this study, the data showed that the average age of patients suffering from prostate cancer was 65.92 years with the largest distribution in the 60-82 year age group. The increase in the incidence of prostate cancer in old age is related to the process of prostate degeneration so that prostate cells are more susceptible to mutation and develop as a malignancy (10,11).
Digital Rectal Examination (DRE) examination showed that most prostate cancer patients had an enlarged prostate with a ridged surface (7.92%), and asymmetry (61.54%). This is in accordance with the theory that prostate cancer patients experience changes in the consistency of the prostate from solid to hard, accompanied by loss of the median sulcus, and the appearance of nodules. The findings in our study are the same as those of Aminshari et al (12).
This study showed that prostate cancer was most widely distributed in the group with serum PSA levels >19.71 ng/dL (76.92%). In research conducted by Mochtar et al. found PSA levels in patients with benign prostate enlargement 21.9 ± 1.6 ng/ml, while for prostate cancer patients the average PSA was higher (371.3 ± 43.1 ng/ml) (13).
From the results of this study, it is known that the cut off levels of PSA and PSAD in prostate disease patients at Saiful Anwar Malang General Hospital is higher than the recommended cut off. With PSA cut-off level of 19.71 ng/ml, and PSAD cut-off level of 0.4113, there were 20 cases requiring a biopsy. With PSA cut-off level of 10 ng/ml and PSAD cut-off level of 0.15, 41 cases underwent prostate biopsy. There were 21 patients (51.22%) who underwent unnecessary biopsies. A study conducted in China on patients with prostate disease found that the optimal PSA cutoff level was 4.5 ng/ml (sensitivity 94.4%, specificity 14.1%, PPV 29.5%, NPV 86.9%), which is lower than the findings in this study. A study conducted by Mochtar et al in Jakarta on patients with prostate disease found that the optimal PSA cutoff level was 42.7 ng/ml (74% sensitivity, 73% specificity, 85.2% PPV, 57.5% NPV, 0.2 AUC). 81) (13,14).
For PSA cut-off level of 4-10 ng/ml, the PSAD should be used to determine whether a biopsy is necessary or not. The PSAD cut off level recommended for biopsy is above 0.15. With PSAD cut-off point >0.15, 6 patients with PSA level of 4-10 ng/ml underwent prostate biopsy. With cut-off level >0.4113, only 2 patients had to undergo a prostate biopsy. This means that 4 patients (66.67%) could have avoided unnecessary biopsies with the new PSAD cut-off level. Our study found that PSAD levels can predict PA outcomes in patients with prostate cancer or benign prostate enlargement. However, different results were found by Aminisharifi’s study which found the optimal PSAD cutoff level at 0.08 (98% sensitivity, 16% specificity, 26% PPV, 96%) (12).
High PSA levels can be caused by various factors such as prostate infection, bladder stones, large prostate volume, advanced age and race. Among the factors that can affect PSA levels, infection can significantly affect PSA levels. In this study, all patients used a urethral catheter with an average duration of use of 2.28 months. Infection can cause prostatitis and eventually increase PSA levels. Several other risk factors, such as genetics, diet, alcohol, smoking, and lipid levels, were thought to increase prostate cancer but were not examined in this study (15-19).
This study has several limitations. First, the relatively small subject size and less diverse subject variations due to the data source from one hospital so that multi-center studies covering patients with various characteristics will be needed in the future. Second, the study of Ellis et al, showed that among patients who were not diagnosed with prostate cancer at the initial prostate biopsy, 20% were diagnosed with prostate cancer when the prostate biopsy was repeated. In this study it is possible that prostate cancer would be diagnosed if the prostate needle biopsy was repeated in a patient who was negative on the first prostate needle biopsy.
6. CONCLUSION
Results from this study, it is known that the cut off levels of PSA and PSAD in prostate disease patients in Saiful Anwar General Hospital Malang is higher than the recommended cut off; prostate cancer is the largest malignancy in men worldwide and has a higher incidence in the older age and high serum PSA levels group.
Acknowledgement:
This study was supported by Department of Urology, Faculty of Medicine, Universitas Brawijaya – Saiful Anwar General Hospital Malang
Ethics:
Ethical approval for this study was obtained from The Ethics Committee of Saiful Anwar General Hospital, Malang with approval number 400/199/K.3/302/2021.
Author’s Contribution:
All authors were involved in all steps of preparation of this article including final proofreading.
Conflict of Interest:
The authors declare no conflict of interest.
Financial Support and Sponsorship:
Special gratitude to Faculty of Medicine, Universitas Brawijaya, Saiful Anwar General Hospital, Malang, Indonesia who made this research possible.
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