Abstract
Aim: To explore the clinical value of magnetic resonance imaging (MRI) combined with serum prostate specific antigen (PSA), epithelial cadherin (sE-cadherin) and early prostate cancer antigen-2 (EPCA-2) in prostate cancer (PC) diagnosis. Patients and Methods: Fifty patients with PC and 50 with benign prostatic hyperplasia (BPH) confirmed by pathology from January 2020 to July 2021 were studied retrospectively. All patients underwent MRI and measurement of the serum levels of PSA, EPCA-2, and sE-cadherin. The diagnostic accuracy and efficacy of these methods was compared between the groups. Results: In MRI diagnosis of PC, lesions were mainly located in the peripheral zone; T2-weighted imaging of this zone showed low signal intensity, with different degrees of prostate enlargement. BPH had a clear boundary, complete capsule and central zone hyperplasia and uneven signal nodules. PC and BPH had different degrees of prostate enlargement. Serum levels of PSA, sE-cadherin and EPCA-2 in the cancer group were significantly higher than those in the BPH group (p<0.05). The diagnostic concordance of combined assessment of MRI, PSA, sE-cadherin, and EPCA-2 in differentiating PC from BPH was 93%, which was significantly higher than these approaches used alone (84%, 79%, 81% and 82%, respectively; p<0.05). The area under the receiver operating characteristics curve for the combined approach in PC diagnosis was 0.900, which was significantly higher than those for the individual methods (0.840, 0.730, 0.760 and 0.810, respectively; Z=2.343, p=0.004). Conclusion: MRI combined with PSA, sE-cadherin and EPCA-2 can improve the sensitivity and accuracy of PC diagnosis and has potential as a guiding scheme for early diagnosis of PC.
Prostate cancer is a common malignant tumor in clinical urology. With the population ageing problem and the change in diet structure, the incidence of this disease is increasing annually. It is one of the important causes of death in male patients with cancer (1). Benign prostatic hyperplasia is the most common benign lesion in urology, and its early symptoms are very similar to those of prostate cancer (2). Most patients with prostate cancer have distant metastasis, mainly in the bone, at first diagnosis, so the early differential diagnosis of prostate cancer and benign prostatic hyperplasia is of great significance to judge tumor progression, treatment, and prognosis of patients (3, 4).
The serum level of prostate-specific antigen (PSA) is a commonly used auxiliary index for prostatic diseases in the clinic (5, 6). Epithelial cadherin (sE-cadherin) is highly expressed in the serum of patients with various tumor types, which makes it an ideal tumor serum marker (7). As a serum biomarker of prostate cancer, early prostate cancer antigen-2 (EPCA-2) has high sensitivity and specificity (8). It is necessary to combine other examination methods to accurately distinguish prostate cancer from benign prostatic hyperplasia. Magnetic resonance imaging (MRI) has high diagnostic value in the diagnosis of prostatic diseases, and its advantages lie in good tissue resolution and multi-directional imaging (9). There is little literature about the value of MRI combined with serum markers in the diagnosis of prostate cancer. Therefore, this study made an in-depth analysis of the value of PSA, sE-cadherin, EPCA-2 and MRI in the diagnosis of prostate cancer, aiming at providing theoretical support for the optimization of the early diagnosis scheme of prostate cancer.
Patients and Methods
General information. The clinical data of 50 patients with prostate cancer and 50 patients with benign prostatic hyperplasia admitted to Weifang People’s Hospital from January 2020 to July 2021 were analyzed retrospectively, and they were included in the prostate cancer group and benign prostatic hyperplasia group, respectively. The Ethics Committee at Weifang People’s Hospital, Shandong, P.R. China, approved the use of tissue samples, the experimental procedures, and granted full ethical approval (approval no.: TRECKY2019-108).
The age of the prostate cancer group ranged from 42 to 60 years, with an average and standard deviation of 52.47±5.62 years. The volume of the prostate was 58-69 ml, with an average of 64.32±3.88 ml. There were 17 cases of hematuria, 39 cases of dysuria and 19 cases of urgency or pain in urination. The prostate cancer Gleason classification (10) was grade 2 in five cases, grade 3 in 16 cases, grade 4 in 21 cases and grade 5 in eight cases. The age of patients in the benign prostatic hyperplasia group ranged from 42 to 62 years, with an average of 54.70±5.13 years. The course of the disease was 4-9 years, with an average of 6.21±2.11 years. The volume of the prostate was 58-70 ml, with an average of 65.30±3.90 ml. There was hematuria in 9 cases, dysuria in 41 cases, and urgency or pain in urination in 10 cases of this group. There were eight cases of atypical giant cell stromal hyperplasia, 17 cases of post-atrophic hyperplasia, six cases of sclerosing hyperplasia, 14 cases of basal cell hyperplasia and five cases of sieve hyperplasia.
Inclusion criteria: (i) Disease met the diagnostic criteria of prostate cancer in “Interpretation of Key Points of European Urology Guidelines for Prostate Cancer 2018” (11) and benign prostatic hyperplasia in “Guidelines for Diagnosis and Treatment of Benign Prostatic Hyperplasia with Integrated Traditional Chinese and Western Medicine (Trial Edition)” (12) and was confirmed by histological biopsy results. (ii) MRI, PSA, sE-cadherin, EPCA-2 and other related examination items were improved. (iii) Prostate rectal digital examination and cystoscopy were not performed 2 weeks before blood collection. (iv) The medical records were intact.
Exclusion criteria: (i) There were serious heart, liver and kidney dysfunction, blood system diseases, infectious diseases, or other malignant tumors. (ii) Anticoagulant and hormone treatment were received within 2 months before admission. (iii) The patients had been treated with androgen deprivation therapy, surgery, or other tumor reduction treatments in the past. (iv) The quality of image data was poor.
Detection of PSA, sE-cadherin, and EPCA-2. Before the puncture biopsy, 3 ml of fasting venous blood was collected, centrifuged at 3,000 × g for 10 min, and the supernatant was stored in a freezer at −40°C. The serum PSA level was detected by the chemiluminescence method using a kit purchased from Roche (Basel, Switzerland). Enzyme-linked immunosorbent assay was used to detect the levels of sE-cadherin and EPCA-2 using kits purchased from Affymetrix (Santa Clara, CA, USA), All procedures were carried out according to the instructions of the kit. Before detection, the specimen was melted on ice, centrifuged at 10,000×g for 10 min, and then the impurities were removed before assays.
MRI examination. Before the examination, to ensure bladder filling, patients were instructed to drink plenty of water. Skyra3.0T Siemens superconducting magnetic resonance scanner was used, and plain MR plus enhanced examinations were performed at rest for half an hour. In axial imaging (T2-weighted fat-saturated fast-recovery fast spin-echo), the slice thickness and slice spacing were 5 mm and 2 mm, respectively, and the matrix parameter was 512×256. The above sequences were repeated in coronal and sagittal planes. On the transverse axis (T1-weighted turbo spin-echo transverse lymph nodes) the layer thickness and interval were 6 mm and 2 mm, respectively, and the matrix parameter was 256×192. The thickness and spacing parameters of axial enhanced scanning (dynamic, T1-weighted, fat-saturated, volumetric interpolated breath-hold examination transverse) were 6 mm and 2 mm, respectively, and the matrix parameters were 256×192.
Data processing and image analysis. The criteria for positivity were: EPCA-2 ≥30 ng/ml (13), PSA ≥10 ng/ml (14) for PSA, and sE-cadherin≥9.67 μg/l (15). The MRI results were evaluated by two professional MRI diagnosticians. The presence of the following two signs in the plain T2-weighted fat-saturated fast recovery fast spin echo MRI sequence was judged as prostate cancer (16): (i) Hemorrhage and nodular low signal focus; (ii) unclear boundary of the central zone, peripheral zone and transitional zone; (iii) glandular tissue breaking through the capsule and even invading surrounding organs; and (iv) lymph node enlargement or uneven bone signal.
Statistical methods. SPSS25.0 software (IBM, Armonk, NY, USA) was used for statistical analysis, which expressed the counting data in percentage form and carried out chi-squared tests. Using the mean and standard deviation to express the data conforming to the normal distribution and using the t-test, receiver operating characteristics curves were drawn to analyze the efficacy of MRI, PSA, sE-cadherin, and EPCA-2 alone and in combination in the diagnosis of prostate cancer.
Results
MRI features of prostate cancer and benign prostatic hyperplasia. MRI features of prostate cancer were that the lesions were located in the peripheral zone, and T2-weighted examination showed that the peripheral zone had a low signal intensity, showing different degrees of prostate enlargement. The lesions invaded the capsule, bladder and surrounding tissues with disappearance or asymmetry on T1-weighted imaging, abnormal signal and muscle thickening, and pelvic lymph node metastasis with partial fusion or enlargement of lymph nodes. The MRI features of benign prostatic hyperplasia were central zone hyperplasia with uneven signal nodules, complete capsule and clear boundary, and a prostate enlarged to different degrees (Figure 1). The MR image of prostate cancer showed the peripheral zone of the prostate to have an equivalent signal but a poor pathological result (Figure 2).
Typical magnetic resonance scanning images of a 75-year-old patient with prostate cancer with the main complaint of “dysuria, prolonged urination time, urgent urination and frequent urination without obvious causes and incentives”. In the magnetic resonance imaging scan (A and B), the volume of the prostate was obviously enlarged and >5 cm transversely. On T2-weighted imaging, a normal high T2 signal existed in the peripheral zone and multiple hyperplastic nodules were found in the central zone. No diffusion restriction area was found in the hyperplastic prostate (C and D). Enhanced scans showed heterogeneous enhancement of benign prostatic hyperplasia nodules (E-G). Biopsy showed benign prostatic hyperplasia with chronic inflammation and calculus formation (H).
Typical magnetic resonance scanning images of a 70-year-old patient with prostate cancer with the main complaint of “elevated prostate-specific antigen, (total prostate-specific antigen=8 ng/ml), accompanied by increased nocturia and incomplete defecation”. In magnetic resonance imaging (A and B), the left peripheral zone of the prostate showed an equal signal on T1-weighted imaging and a low signal nodule on T2-weighted imaging. There was high signal intensity in diffusion-weighted imaging sequence (B value=0-500-1,000s/mm2), low signal intensity in apparent diffusion coefficient sequence and limited diffusion (C and D). On the enhanced scan, there was enhancement of nodules (E-G). The pathological result was poorly differentiated adenocarcinoma of the prostate (H), Gleason score: 4+4=8.
Comparison of PSA, sE-cadherin, and EPCA-2 levels between the two groups. The levels of PSA, sE-cadherin, and EPCA-2 in patients with prostate cancer were significantly higher than those in patients with benign prostatic hyperplasia (p<0.05; Table I).
Comparison of prostate-specific antigen (PSA) and epithelial cadherin (sE-cadherin) and early prostate cancer antigen-2 (EPCA-2) results between the two groups. Data are the mean±standard deviation.
Comparison of MRI, PSA, sE-cadherin, and EPCA-2 alone and in combination. With pathological biopsy results as the gold standard, the diagnostic concordance rates for MRI, PSA, sE-cadherin, and EPCA-2 in differentiating prostate cancer from benign prostatic hyperplasia were 84%, 79%, 81% and 82%, respectively. There was no statistical significance among the individual methods (p>0.05), but the diagnostic concordance for the four methods combined was 93%, which was significantly higher than that of the four methods alone (p<0.05; Table II).
Comparison of diagnostic results of magnetic resonance imaging (MRI), prostate-specific antigen (PSA), epithelial cadherin (sE-cadherin) and early prostate cancer antigen-2 (EPCA-2) alone and in combination.
Diagnostic value of MRI, PSA, sE-cadherin, and EPCA-2 alone and in combination in prostate cancer. The area under the receiver operating characteristics curve (Figure 3), specificity and sensitivity of MRI, PSA, sE-cadherin, and EPCA-2 in the diagnosis of prostate cancer were significantly higher than those of each method alone (Z=2.343, p=0.004; Table III).
Receiver operating characteristics curve for magnetic resonance imaging (MRI), prostate-specific antigen (PSA), epithelial cadherin (sE-cadherin) and early prostate cancer antigen-2 (EPCA-2) alone and in combination in the diagnosis of prostate cancer.
Diagnostic value of magnetic resonance imaging (MRI), prostate-specific antigen (PSA), epithelial cadherin (sE-cadherin) and early prostate cancer antigen-2 (EPCA-2) alone and in combination for prostate cancer.
Discussion
The global morbidity and mortality of prostate cancer continue to rise, and early diagnosis with effective programs is the key to improving the treatment effect and reducing the mortality of patients with prostate cancer (17). MRI is a common examination scheme for the diagnosis of prostatic diseases, and MRI examination can obtain more accurate diagnosis because of its high resolution of tissues (18). The results of Boesen showed that the sensitivity and specificity of MRI diagnosis were above 85.00%, and MRI had clinical value as the first choice of imaging examination (19). In this study, the results showed that patients with prostate cancer had lesions with a low signal in the peripheral zone, which may be due to the closer arrangement of tumor tissues in patients with prostate cancer, and a large decrease in mucin and fluid (20). In addition, the accuracy, sensitivity, and specificity of MRI in the differential diagnosis of prostate cancer and benign prostatic hyperplasia were ≥80.00% (21). It is suggested that MRI has high clinical value in diagnosing prostate cancer. The main reason is that MRI can clearly show the invasion of tumor and surrounding tissues and lymph node metastasis, as well as obtain high-resolution images, to accurately analyze and judge the occurrence of prostate cancer in patients and improve the accuracy of early diagnosis (22).
sE-Cadherin is a free E-cadherin fragment on a tissue surface, which is mainly released into blood circulation after cathepsin degrades E-cadherin, It is closely related to the occurrence and development of tumor (23). Tao et al. (24) showed that the serum sE-cadherin level increased abnormally in patients with prostate cancer, but the level of sE-cadherin in patients with benign mass also increased. Therefore, sE-cadherin has some value in the clinical diagnosis of prostate cancer, but its application is limited. The results of our study showed that the level of sE-cadherin in patients with prostate cancer was significantly higher than that in patients with benign prostatic hyperplasia, and the accuracy, sensitivity, and specificity in the diagnosis of prostate cancer and benign prostatic hyperplasia were all over 75.00%, which was consistent with the results of the above research (23, 24), suggesting that sE-cadherin is a sensitive index in the diagnosis of prostate cancer. One reason for this may be that the protease activity of tumor cells and tissues is obviously increased. The degradation of E-cadherin in patients’ tissues is accelerated, and the tissue function and surface structure are destroyed, which leads to cell adhesion of tumor tissues being greatly reduced or completely lost, resulting in the release of sE-cadherin fragments into the blood circulation in large quantities, therefore the serum sE-cadherin level of patients with tumor is increased (25).
Gratacós-Mulleras et al. indicated that PSA can be used as a specific diagnostic marker for prostate cancer (26). Ediz et al. showed that PSA had good sensitivity and specificity in diagnosing prostate cancer (27). The results of this study showed that the level of PSA in patients with prostate cancer was significantly higher, and the accuracy, sensitivity, and specificity of PSA in the diagnosis of prostate cancer were all about 70.00%, indicating that the efficacy of PSA in the diagnosis of prostate cancer was mediocre, which was consistent with the above research (26, 27). The increase in PSA level may be due to the fact that PSA testing is affected by indwelling catheter, chronic prostatitis, prostate massage and other factors, which lead to an increased risk of misdiagnosis In addition, PSA can only be detected after the prostate epithelial cell barrier is damaged and PSA enters the blood circulation, which affects the diagnostic value of PSA to a certain extent (28).
Nuclear matrix proteins are the main components of the nuclear matrix, and the structural and functional changes of nuclear matrix proteins affect the occurrence and development of cancer. EPCA-2 is the main nuclear matrix protein associated with prostate cancer (29). Mei et al. pointed out that EPCA-2 is expressed at a high level in patients with prostate cancer, which is a sensitive index for the diagnosis of prostate cancer (30). In this study, the results showed that the level of EPCA-2 in patients with prostate cancer was higher than that in patients with benign prostatic hyperplasia, and the sensitivity, specificity, and accuracy in diagnosing prostate cancer were all about 80.00%, which indicates that EPCA-2 had a high diagnostic value in the diagnosis of prostate cancer. The mechanism for this is explained as follows: EPCA-2 is tissue-specific and is released into the blood circulation in large quantities due to the destruction of the vascular barrier of prostate epithelial cells in patients with prostate cancer, which leads to a high level of EPCA-2 expression in cancer cells (31). In addition, EPCA-2 exhibits morphological and biochemical changes after carcinogenesis. In turn, the DNA topology of patients affected, which leads to the deterioration of prostate cancer (31). Our results showed that the accuracy, sensitivity, specificity and AUC of PSA, sE-cadherin, and EPCA-2 combined with MRI in diagnosing prostate cancer were higher than those of MRI alone, suggesting that the combined diagnosis using these four examinations is a reference scheme for improving the value of each index in diagnosing prostate cancer.
A limitation of this study is that the sample size of the included cases is small, and the diagnostic cut-off values for PSA, sE-cadherin and EPCA-2 still need to be further verified, Subsequent multi-center and larger-sample study is warranted.
In conclusion, the combined application of MRI, PSA, sE-cadherin, and EPCA-2 in the diagnosis of prostate cancer can make up for the shortcomings of each in single diagnosis, and effectively improve the clinical diagnostic efficiency. Therefore, MRI combined with PSA, sE-cadherin and EPCA-2 is a good scheme for the early diagnosis of clinical prostate cancer.
Footnotes
Authors’ Contributions
K. Li and Q. Luan organized the patients, performed the MRI. scan and drafted this article; J. Zhang, R. Li and L. Li collected the blood, performed the blood tests, and analyzed the data. Y. Sun and D. Liu directed the project and finalized the draft.
Conflicts of Interest
The Authors confirm that there are no known conflicts of interest associated with this publication and declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.
- Received July 30, 2022.
- Revision received September 8, 2022.
- Accepted September 21, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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