While serum PSA remains the mainstay screening for prostate cancer, appropriate use of biomarkers prevents the overdiagnosis of prostate cancer and over treatment of prostate cancer which is not clinically significant. Even though only PHI and PCA3 had been the only biomarkers which had been FDA approved, it is important that the clinician should be familial with other biomarkers that could provide advantages to a group of patients. PHI test and 4Kscore demonstrated similar capability to predict clinically significant cancer and both can reduce the number of unnecessary biopsies but PHI price is significantly lower. Select MdX and Exosome Dx do have encouraging results but would necessitate more studies for incorporation into the routine clinical practice. The largest limitation when deciding which biomarker to use is the lack of prospective head-to-head trials comparing the various tests. There are many biomarkers available for the detection of csPCa both in the initial and repeat biopsy setting. The largest limitation when deciding which biomarker to use is the lack of prospective head-to-head trials that compare the various tests. In addition, many studies had suggested that even within a given test the cutoff used in one population may not be the most appropriate cutoff for another population. In view of this, extensive validation in multiple diverse cohorts is critical to confirm the findings. Serum and urine biomarkers do improve the detection of csPCa reducing over-treatment and making treatment strategies more cost effective. Large prospective head-to-head comparisons of all biomarkers are required to fully assess the potential of incorporating biomarkers in routine clinical practice. At the moment, serum PSA determination, and digital rectal examination to identify abnormal findings within the prostate backed by radiology imaging of the prostate gland and radiology image-guided prostate biopsies generally enable the clinician to identify various grades and stages of prostate cancer. Nevertheless, biomarker and cytogenetics testing is now able the clinician to identify prostate cancers that would tend to portend indolent biological behaviour which would not need to be treated as well as aggressive tumours that need urgent treatment. There is however, a global need for further urine and blood biomarker studies that would convincingly demonstrate tumours that need not to be treated as well as those that need to be treated and their locations.

Prostate cancer (PCa) is stated to be the most common malignant tumour of the urinary tract. [1] PCa is iterated to rank second in incidence and fifth in mortality among all malignant tumours. [1] The life risk of PCa diagnosis is reported to be one in nine men, but the risk of death might be as low as 2% [1] [2] The current recommendations for PCa diagnosis are based upon the guidelines of the European Association of Urology (EAU-ESTRO-SIOG), which entails the analysis of the serum concentration of prostate-specific antigen (PSA), as well as undertaking a digital rectal examination (DRE) for abnormalities. [3] Nevertheless, digital rectal examination (DRE) is stated to be associated with low sensitivity., [4] while serum PSA level is rather organ-, but not tumour-specific (low specificity), and has a low positive predictive value of about 30%). [5] Thus far, the final diagnosis of prostate cancer depends upon histopathology examination report of adenocarcinoma in the core biopsy of the prostate gland. False positive PSA test results, in patients with benign prostatic hyperplasia (BPH) and/or prostatitis, may result in systematic transrectal ultrasonography (TRUS) – controlled prostate biopsy (Bx). In addition, serum PSA – based screening might lead to over-diagnosis and potentially over-treatment of PCa, which would never be of clinical relevance. There is a clinically unmet necessitation for the development of biomarkers that would help control PCa treatment strategies. Many diagnostic tools are available on the PCa laboratory market. There are new biomarkers for serum, urine and even tissue samples. [6] New biological markers, such as TMPRSS2-ERG fusion gene, and the non-coding RNA (PCA3) [7] or kallikrein included in basic PHI (prostate health index) or 4K tests, [8] had been demonstrated to increase sensitivity and specificity PSA, potentially avoiding biopsy and reducing over-diagnosis. Modern biomarkers used in prostate diagnosis have been listed in. Measurement of serum PSA levels entail an invasive procedure undertaking blood tests but if urine examination would determine the risk of prostate cancer, this would be beneficial to all patients. Recent tests have demonstrated the usefulness of urine biomarkers in ascertaining the risk of prostate cancer. The guidelines recommend utilising these tests, additionally to standard methods, as an effective diagnostic tools for cancer diagnosis. Irregularities resulting from the mentioned tests are an indication for prostate biopsy [3]. Lastly, risk calculators could be helpful in the determination (individually) of the potential risk of cancer; hence reducing the undertaking of a number of unnecessary biopsies. [9] 

Hessels et al. [10] made the ensuing preamble iterations: 

• It has been pointed out that annually, 241 740 men in the United States of America (USA) and 338 700 men within Europe are newly diagnosed with prostate cancer (PCa) and around 28 170 USA and 70 800 European men die from this disease. [11] [12] 
• Early detection of PCa relies on serum prostate-specific antigen (PSA) testing or digital rectal examination (DRE). 
• Since its first clinical application, serum PSA had been a valuable tool in the detection, staging and monitoring of prostate cancer. 
• Even though the routine use of serum PSA testing had undoubtedly increased PCa identification, one of its main disadvantages has been its lack of specificity resulting in a high negative biopsy rate. [13] 
• The early detection of many indolent prostate cancers (PCas) had resulted in treatment of tumours that would not have become life-threatening to an individual patient.
• Serum PSA has a low specificity because it is not a prostate cancer (PCa)-specific event; elevated levels could also be identified in men with benign prostatic hyperplasia (BPH) and prostatitis. 
• Methods to enhance serum PSA specificity had assisted clinicians in deciding which patients should undergo prostate biopsy; nevertheless, have not necessarily improved diagnostic accuracy or facilitated optimal therapy decision-making. 
• More accurate tests which can stratify patients according to their risk of developing prostate cancer (PCa), identify men who require repeat prostate biopsy and stratify men at risk for aggressive disease are needed.
• Many biomarkers had been identified and some of them are promising because of their specificity for the disease in tissue. Nevertheless, tissue is unsuitable as substrate for biomarker testing because of its invasiveness and expensiveness. Therefore, testing of disease-related biomarkers in body fluids that could be obtained in a non-invasive manner seems a good alternative as possible screening tool. 
• Because of the ease of collection, and the fact that prostate cells are directly released into the urethra via prostatic ducts after DRE, urine has become the future for non-invasive biomarker testing. 

The ensuing article on urine biomarkers that are being used for the assessment prediction of prostate cancer is divided into two parts: (A) Overview of prostate cancer and (B) Miscellaneous narrations and discussions related to urine and blood biomarkers in use for the prediction and assessment of prostate cancer. 

Aim 

To update the literature on urine and blood biomarkers associated with prostate cancer.

Internet databases were searched. The search words that were used included urine biomarkers for prostate cancer, urine biomarkers for adenocarcinoma of prostate, blood biomarkers for prostate cancer, and blood biomarkers for adenocarcinoma of prostate. – references were identified which were used to write the article which has been divided into two parts: (A) Overview of prostate cancer and (B) Miscellaneous narrations and discussions related to urine and blood biomarkers in use for the prediction and assessment of prostate cancer.

[A] Overview

Definition / general iterations 

• Adenocarcinoma of the prostate gland is known to be the most common malignancy of the prostate gland. [14]
• Adenocarcinoma of the prostate gland originates from prostatic secretory epithelium. [14]

Essential features

The ensuing summations had been made regarding the essential features of adenocarcinoma of the prostate gland: [14]

• Clinical and radiological features of adenocarcinoma of the prostate gland are stated to be neither sensitive nor specific for the diagnosis of adenocarcinoma of the prostate gland. 
• Adenocarcinoma of the prostate gland is stated to be often diagnosed by non-targeted needle biopsies investigating raised serum prostate specific antigen (PSA) and the histopathology examination features of the biopsy specimen are used to establish the diagnosis. 
• Absence of basal cell layer is iterated to be a pathognomonic histological feature of adenocarcinoma of the prostate gland.
• Pathognomonic diagnostic features of adenocarcinoma of the prostate gland include the ensuing: circumferential perineural invasion, glomerulations and collagenous micronodules (mucinous fibroplasia)
• Other histopathology examination features of adenocarcinoma of the prostate gland include the ensuing: infiltrative architecture, nucleolar prominence, amphophilic cytoplasm and some intraluminal contents (crystalloids, blue mucin, pink amorphous material)

Terminology

Terminologies that tend to be used for adenocarcinoma of the prostate gland include: [14]

• Prostate cancer
• Prostate adenocarcinoma
• Sub-types of prostatic adenocarcinoma include the ensuing: acinar adenocarcinoma, ductal adenocarcinoma, atrophic adenocarcinoma, pseudo-hyperplastic adenocarcinoma, microcystic adenocarcinoma, foamy gland adenocarcinoma, mucinous adenocarcinoma, signet ring variant of adenocarcinoma, pleomorphic giant cell adenocarcinoma, Sarcomatoid adenocarcinoma

Epidemiology

The epidemiology of adenocarcinoma of the prostate gland had been summated as follows: [14]

• Adenocarcinoma of the prostate gland is the second most common cancer and second leading cause of cancer related death in American men (SEER data). [15] 
• 92% of U.S. cases of adenocarcinoma of the prostate gland is diagnosed in men aged 55+ years; 19.5% in men aged 75+ years (SEER data available at) [16] 
• Adenocarcinoma of prostate gland is found at autopsy in 40% of men age 60+ years [17] 
• Incidental prostate cancer is iterated to be reported in about 25% of cystoprostatectomies performed for treatment of bladder cancer [18]  
• It has been iterated that globally, highest age standardized rates of adenocarcinoma of prostate gland is found in Oceania, North America, Europe [19] 
• It has been pointed out that lower rates of adenocarcinoma of the prostate gland are reported in developing countries and this may be due to different screening programs and diagnostic pathways. [14]
• Higher incidence of adenocarcinoma of the prostate gland is reported in men of African heritage [19] 

Sites

The sites of origin of primary adenocarcinoma of the prostate gland had been summated as follows: [14]

• Most adenocarcinoma of prostate gland tumours are multi-focal [20] 
• 75% to 80% of adenocarcinomas of the prostate gland are within the posterior / posterolateral peripheral zone of the prostate gland. [14]
• Approximately 13% to 20

• There is an urgent need to identify more accurate non-invasive tests for the diagnosis of prostate cancer and to enable the stratification of patients who have life-threatening prostate cancer. 
• In view of the ease of collection, and the fact that prostate cells are directly released into the urethra via prostatic ducts after digital rectal examination (DRE) or prostate massage, urine has now become the future of non-invasive biomarker testing. 
• Many studies have demonstrated the feasibility of urine for the non-invasive detection of prostate cancer. 
• It had been demonstrated that RNA biomarkers could also be identified in urinary exosomes, making them promising for biomarkers research as well.
• Biomarker research is in focus at many laboratories and many biomarkers are promising due to their specificity for the disease in tissue. 
• Only few of these biomarkers had been shown to be useful as urinary marker. 
• Two prostate-specific RNA-based biomarkers have been found (PCA3 and TMPRSS2-ERG gene fusions). 
• The recent FDA approval of PCA3 had led to its introduction in clinical practice and the combination of both markers has been marketed for clinical use as well. 
• In comparison with single biomarkers, the combination of many biomarkers considerably improves the prediction of prostate cancer within urine samples which is consistent with the heterogeneity of the disease.
• In the era of individualized therapy, the biomarker combinations are necessary to not only predict prostate cancer at biopsy; nevertheless, also the aggressiveness of the cancer. 
• Preliminary results had shown that the prostate cancer (PCa)-specific TMPRSS2-ERG gene fusion could be indicative of aggressiveness of cancer upon biopsy, although further studies are warranted. 
• In PCa biomarker development, the greatest unmet need has remained: a biomarker that stratifies men at risk of aggressive PCa, eventually leading to a reduction in the undertaking of unnecessary interventions.