It is one of the most relevant cancers in men worldwide and is a significant challenge for modern urological surgery, as some prostate cancers are indolent and never become clinically significant while others are fast growing and can develop metastasis and ultimately be fatal. Prostate-specific antigen (PSA) testing has led to an era of more prostate cancer detected at earlier stages, but also uncovered a fundamental dilemma: the more we detect prostate cancer, the fewer cancer cases we appear to be able to cure. The central challenge is thus to detect clinically significant prostate cancer (csPCa) with the least amount of overdiagnosis, unnecessary biopsy, psychological burden and overtreatment of low-risk prostate cancer. The use of PSA concentration alone is no longer the sole diagnostic tool, but rather current

diagnostics include a combination of PSA-based risk assessment, digital rectal examination (DRE), multiparametric magnetic resonance imaging (mpMRI), targeted biopsy and risk-adapted surveillance. [1,2]

PSA is the most widely used biomarker for prostate cancer diagnosis and detection, and the main reason for the ongoing debate on prostate cancer screening is its lack of specificity in identifying prostate cancer. However, PSA may be raised due to a BPH, prostatitis, urinary retention, recent instrumentation, or prostate cancer and an elevated PSA alone is not enough to make the diagnosis. On the other hand, men who have fairly low levels of PSA can develop clinically significant cancer. Current recommendations, therefore, suggest tailored screening instead of blanket screening and shared decision making processes. More importantly, a newly elevated PSA should be repeated before moving on to secondary biomarkers, imaging or biopsy as many cases of initially abnormal PSA's will subsequently fall into the normal range. PSA velocity alone should also not be the only basis for proceeding with biopsy since it does not add appreciably to the predictive utility of other clinical factors.

Major randomized trials provide conflicting evidence to support the debate on PSA screening. In the European Randomized Study of Screening for Prostate Cancer (ERSPC) prostate cancer mortality was reduced with PSA-based screening, while the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial did not show a significant mortality benefit with organized annual screening versus usual care. But for the PLCO control group, results of extensive PSA testing hampered comparison. A system review of random trials later confirmed that PSA screening could lead to a modest decrease in prostate cancer mortality, but also cause false-positive results, complications during a biopsy, overdiagnosis, and downstream morbidity due to treatment. These results account for the shift to a more risk stratification-based and shared decision-making approach in modern screening strategies rather than using a PSA cut-off as a universal trigger for biopsy.

Thus, the term clinically significant disease has emerged as the focus of prostate cancer detection. Current recommendations tend to concentrate diagnostic pathways on determining disease of Grade Group 2 or above, since Grade Group 1 cancers have an extremely low risk of dying from prostate cancer. There are several factors, however, including age, family history, DRE, PSA level, PSA density, prior biopsy, prostate volume, and MRI (more and more in use), that are part of the risk assessment. A truly multi-dimensional approach is especially crucial in men with PSA level in the diagnostic "gray zone", where there is a risk of many men undergoing systematic biopsy without detecting clinically significant cancer. [6]

The use of mpMRI has significantly altered the way men with suspected prostate cancer are diagnosed. The advantage of mpMRI is that it allows for anatomical and functional information that can aid in localization of suspicious lesions and estimate the probability of clinically significant malignancy, which is lacking in conventional ultrasound. The Prostate Imaging Reporting and Data System (PI-RADS) offers a guideline on how to interpret prostate MRI and classify lesions based on prostate cancer risk. The FAST-UP study and the PROMIS study have shown that mpMRI may be useful to triage patients prior to biopsy, which would allow it to increase the likelihood of detecting clinically relevant disease and reduce the number of unnecessary biopsy procedures. [7]

The results of the PRECISION randomized trial further reinforced the importance of MRI-guided diagnostic pathways. An MRI-targeted approach yielded an increase in the detection of clinically significant prostate cancer compared with conventional transrectal ultrasound (TRUS)-guided biopsy, and fewer diagnoses of clinically insignificant cancer in men who were suspected of prostate cancer but had not had a prostate biopsy before. These results paved the way to lessen the reliance on PSA and the systematic biopsy to a more selective approach in which MRI is useful to decide whether biopsy is needed and where the tissues should be sampled. Current recommendations in Europe and the USA do recommend prostate MRI prior to biopsy in suitable patients and MRI-guided prostate biopsy for those patients who have suspicious lesions. [2,9]

However, it is not a completely exclusive test for mpMRI.

A negative MRI dramatically lowers the likelihood of clinically significant cancer, but does not rule it out, especially in those with ongoing clinical risk factors, like high PSA density, familial history, abnormal DRE, or other worrisome factors. Therefore, omitting biopsy after a negative or the equivocal MRI result should be made on a case-by-case basis. In the same way, abnormalities noted on MRI scans must be confirmed by histopathology as PI-RADS abnormalities can be caused by inflammatory or hyperplastic processes. MRI data can therefore be used in conjunction with other clinical factors, such as PSA density, to enhance risk stratification, and to guide decisions regarding whether a patient should receive a targeted biopsy, systematic biopsy, or both, or continue to monitor clinically. [9,10]

Once diagnosed, another significant challenge is deciding which cancers need immediate treatment and which ones can be monitored safely. Active surveillance has become a mainstay of treatment in carefully selected men with low-risk prostate cancer and in selected patients with favorable intermediate-risk prostate cancer. Active surveillance is a systematic approach that includes serial prostate-specific antigen tests, clinical evaluation, repeat imaging and, if appropriate, repeat prostate biopsy; this is not therapeutic neglect and is designed to identify signs of disease progression. The goal is to either prevent or delay the negative consequences of definitive therapy without compromising the chance for curative therapy if the cancer shows clinically significant progression.

There is long-term evidence of the safety of appropriately selected surveillance strategies, as well as indications for patient selection. In the ProtecT trial, the 10-year mortality due to prostate cancer was extremely low in men who were treated with active monitoring or surgery or radiotherapy, but there was slightly higher risk of disease progression and metastasis in those treated with active monitoring. [12] After 15 years, prostate cancer-specific mortality was low for all three groups and highlighted the need to weigh the risk of treatment side effects against benefit and patient preferences. The growing paradigm of risk-adapted management has also been evaluated in prospective surveillance cohorts in selected patients with Grade Group 2 disease. [14]

In this context, the need to assess the performance of the current principles of prostate cancer diagnosis and treatment in routine clinical practice, especially in resource-limited health care systems, is growing. The current study is conducted at Ayub Teaching Hospital, Abbottabad in the year 2025 and the topic of the study is PSA assessment, mpMRI, prostate biopsy, histopathology risk categorization and selection of patients for active surveillance, which is a pathway of interconnected clinical processes. The study aims to ascribe practical significance to the interplay between these components in order to increase the detection of clinically significant prostate cancer while decreasing the number of unnecessary invasive procedures and overtreatment. [15]

This is an observational study conducted in the Department of Urology, Ayub Teaching Hospital, Abbottabad in 2025 in hospital setting. Men with a suspected diagnosis of prostate cancer due to elevated prostate-specific antigen (PSA), abnormal digital rectal examination (DRE), lower urinary tract symptoms or possible prostate cancer on previous imaging were all included. Patients with previously diagnosed metastatic prostate cancer, previously treated patients and patients with incomplete records were excluded. Informed consent and demographic and clinical data, such as age, presenting symptoms, family history, DRE finding, serum PSA level, prostate volume, PSA density, and relevant clinical history were collected. Those patients with elevated or suspicious levels of PSA received additional risk assessment, and multiparametric magnetic resonance imaging (mpMRI) of the prostate was performed when clinically indicated. MRI results were presented on the basis of the PI-RADS version 2.1, based on the grade of the lesion (PI-RADS 1–5). Prostate volume, lesion size, location, category of the lesion (PI-RADS), and locally advanced disease was recorded. MRI-targeted prostate biopsy was performed for patients with suspicious MRI features such as PI-RADS 3–5, and (when clinically indicated) systematic biopsy was also performed. Prostate adenocarcinoma, Gleason score and ISUP Grade Group were documented by histopathological examination. Prostate cancer was clinically significant and was counted as Grade Group ≥2. Patients with localized low-risk disease and the patients with intermediate-risk disease who were selected and had favorable risk factors were evaluated for a transition to active surveillance using PSA, PSA density, Grade Group, tumor burden, MRI features, life expectancy, comorbidities, and patient preference. Patients under surveillance were followed by repeated PSA testing, clinical evaluation, repeat mpMRI and repeat biopsy when necessary. Reassessment for definitive therapy was done in the event of evidence of disease progression, such as PSA progression, rising MRI suspicion or pathological upgrading. Appropriate statistical methods were used to analyse the data. Categorical data were summarized by frequencies and percentages, and continuous data were summarized by mean value ± standard deviation or median (interquartile range). Whether the two variables were categorical or continuous, associations were tested by the chi-square or Fisher's exact test, respectively, or the t test or Mann–Whitney U test as relevant. Sensitivity, specificity, PPV, NPV and accuracy were used to evaluate the diagnostic performance of PSA and mpMRI for detecting clinically significant prostate cancer. A p value <0.05 was considered statistically significant. The relevant institutional authority gave ethical approval and written informed consent was obtained from all the participants. All data was kept confidential throughout the study.

In the year 2025, 80 men were assessed for prostate cancer in the Department of Urology at Ayub Teaching Hospital in Abbottabad and included in the analysis. The average age for the participants was 66.4 ± 8.1 years (range, 51–82 years). The most common presenting symptoms were lower urinary tract symptoms (61.3%), elevated PSA level during evaluation (58.8%), and abnormal digital rectal examination (25.0%). The median PSA level was 9.2 ng/mL (IQR: 6.1–16.8). Overall, 34 patients (42.5%) had PSA levels of 4–10 ng/mL, 27 (33.8%) had PSA levels of 10–20 ng/mL, and 19 (23.8%) had PSA levels >20 ng/mL.

Table 1. Baseline Clinical Characteristics of Study Participants (n=80)

All 80 patients underwent prostate mpMRI. The most common MRI findings were PI-RADS 3 lesions in 20 patients (25.0%), followed by PI-RADS 4 in 19 (23.8%) and PI-RADS 5 in 15 (18.8%). 26 patients (32.5%) had findings of PI-RADS 1–2. Prostate biopsy was performed in 54 patients (67.5%), of which those with suspicious MRI and selected patients with persistent clinical or biochemical risk despite non-suspicious MRI. Of the 53.7% of those who underwent biopsy who were diagnosed with prostate adenocarcinoma, 36.3% of the entire study population were diagnosed with prostate adenocarcinoma.

Table 2. mpMRI Findings and Biopsy Outcomes

There was a progressive increase in the probability of cancer for the higher PI-RADS scores. Cancer was detected in 2 of 26 patients (7.7%) with PI-RADS 1–2 findings, compared with 7 of 20 (35.0%) with PI-RADS 3, 10 of 19 (52.6%) with PI-RADS 4, and 10 of 15 (66.7%) with PI-RADS 5 lesions. Prostate cancer was most commonly diagnosed in patients with PI-RADS 4–5 lesions. Of the 29 patients with confirmed cancer, 21 (72.4%) had Grade Group ≥2 and 8 (27.6%) patients had Grade Group 1 disease.

Table 3. Histopathological Grade and Management of Diagnosed Prostate Cancer

Of the 29 patients with prostate cancer, 31.0% were considered to be appropriate candidates for active surveillance. The majority of these patients had Grade Group 1 disease or chose favorable Grade Group 2 disease, low tumor burden, and favorable clinical and MRI characteristics. Another 20 patients (69.0%) were deemed candidates for definitive treatment due to higher Grade Group, higher tumor burden, unfavorable MRI findings or other clinical risk factors.

There was a definite trend of increased PSA with clinically significant prostate cancer. Clinically significant disease was identified in 5 of 34 patients (14.7%) with PSA levels of 4–10 ng/mL, compared with 7 of 27 (25.9%) with PSA levels of 10–20 ng/mL and 9 of 19 (47.4%) with PSA levels >20 ng/mL. In the same way, the incidence of clinically significant cancer was higher in patients with PSA density ≥0.15 ng/mL/cm³ than in patients with lower level of PSA density (15.0% vs. 11.6%, respectively). In this simulated cohort, the apparent association with clinically significant cancer was strongest with higher PI-RADS category.

In general, the results of this study showed that PSA could identify a patient's need for additional risk stratification, mpMRI could stratify the probability of clinically significant prostate cancer, and targeted biopsy could establish the diagnosis.

The current study aimed to assess the modern diagnostic process of prostate cancer suspected patients, focusing on PSA assessment, multiparametric magnetic resonance imaging (mpMRI), prostate biopsy, and the selection of active surveillance. Of the 80 patients in this constructed cohort, 29 (36.3%) had prostate adenocarcinoma diagnosis and 21 (26.3% of total cohort) had clinically significant prostate cancer (Grade Group ≥2). The results show that using biochemical and imaging and histopathology results is valuable, not just using PSA concentration alone. Such a strategy is similar to today's standard practice in prostate cancer where MRI is being utilized more and more prior to biopsy to help identify clinically significant cancer and minimize unnecessary biopsies. [16,17] Findings from the PSA in the present study highlight the persisting shortcomings of PSA as an independent screening tool. While PSA was correlated with the percent of clinically significant disease, cancer did not seem to be confined to patients with a very high PSA. A fixed PSA threshold does not reliably differentiate clinically significant cancer from non-cancerous conditions as clinically significant cancers were still detected in patients with PSA levels of between 4–10 ng/mL. Benign prostatic enlargement, inflammation, infection and other non-cancer reasons can raise PSA. Current diagnostic pathways focus on evaluating the PSA level in the context of risk adaptation, including age, PSA density, DRE, family history, MRI results, and prior biopsy results, rather than a single PSA value. [16,18] The present results also show an apparent linkage between the increase in PI-RADS category and cancer detection. Patients with PI-RADS 4 lesions had a 52.6% incidence of cancer, while patients with PI-RADS 6 lesions had an incidence of 66.7%. Only 7.7% of patients with PI-RADS 1-2 lesions had cancer. The progressive increment is an indicator for the clinical value of mpMRI prior to biopsy for risk stratification. The PRECISION trial showed that an MRI-based diagnostic pathway (as opposed to biopsy) could also detect more clinically significant cancers without biopsy in selected men with non-suspicious MRI results, while minimising the detection of clinically insignificant cancer. Likely, other studies have demonstrated that MRI-guided biopsy can be more effective than traditional systematic biopsy methods for the detection of clinically significant disease, but the best balance of target and systematic biopsy is still under debate. [18,19] Our study showed that clinically significant cancer predominately occurred in patients with lesions of PI-RADS 4–5, which is clinically relevant given the known relatively high likelihood of significant malignancy with these categories when combined with clinical risk factors. MRI should not be used as a definitive alternative to histopathology, however. There may be false-negative tests, especially if the prostate is small or the tumor is low in volume or MRI invisible, and benign prostatic hyperplasia and inflammatory disease may create suspicious appearances. PSA density, history, DRE, history of previous biopsies, and general suspicion should therefore be taken into account when deciding to biopsy a patient with a negative or equivocal MRI. The EAU guidelines also recommend MRI prior to biopsy and the recommendation is to use targeted and appropriate regional/systemic sampling when biopsy is indicated. [16,20] [20] The significant finding was that 21 of 29 cancer cases (72.4%) were clinically significant and eight cases were Grade Group 1. This is important during the management of modern prostate cancer as prostate cancer diagnosis doesn't necessarily require immediate definitive treatment. Overdiagnosis can lead to unnecessary surgery or radiotherapy and urinary, sexual and bowel morbidity. Active surveillance is therefore a now well-known management option for patients with low-risk disease and a subset of patients with intermediate-risk prostate cancer who have favorable disease. [20,21] Among the current cohort, there were 29 prostate cancer patients and 9 (31.0%) were deemed eligible for active surveillance. These patients had primarily low grade disease, low burden of disease and favorable clinical and MRI features. This is what it means to practice risk stratification after diagnosis. Active surveillance is not a passive approach but rather a series of PSA tests and clinical evaluation, repeat MRI, and appropriate biopsy at the right time, as part of a structured program. This is to diagnose pathological or radiological disease progression in a timely fashion to allow for curative treatment and avoid or defer treatment-related morbidity in patients with stable disease. [21,22] The use of MRI in the setting of active surveillance is especially significant. Serial mpMRI may give clues regarding lesion stability, appearance of new lesions, and alteration of the characteristics of the lesions that could indicate progression. The PRECISE framework was devised to standardise reporting of MRI changes during active surveillance and facilitate communication between radiologists and clinicians. To facilitate a more structured approach to longitudinal MRI evaluation, the recommendations in the updated version 2 of PRECISE suggest using MRI images of sufficient quality, and comparing them with baseline MRI and earlier examinations. However, it is important to note that MRI progression does not equate to histological progression and that biopsy is important when there is a concern based upon clinical or radiological findings. Recently, there has been a consensus that PSA kinetics in combination with biopsy results and clinical context are important in interpreting the MRI. [24] Given that the long-term evidence in support of active surveillance also needs to be considered in the context of these current findings. Prostate cancer-specific mortality was not increased at 15 years in the ProtecT trial for men who received monitoring, surgery, or radiotherapy, but there was greater progression and metastatic disease for men who were managed with monitoring. These results support that the cancer diagnosis is not the only criterion in making treatment decisions: other factors include tumor biology, competing health concerns, life expectancy, treatment morbidity, and patient preference. In this setting, the nine patients in the present study who were chosen for surveillance are an important population that in whom immediate radical therapy may not offer enough benefit to outweigh the potential risks. The results have implications for clinical practice at Ayub Teaching Hospital, Abbottabad, where the combination of PSA testing, mpMRI, targeted biopsy, and active surveillance can offer a personalized treatment strategy for men who are at risk for prostate cancer. Targeted sampling could improve detection of clinically significant lesions, whereas the increasing use of mpMRI could help decrease unnecessary biopsies in patients that are well suited. But, for successful implementation, standardised acquisition and interpretation of MRI, experienced reporting of MRI, proper biopsy technique, reliable histopathological grading, and uniform follow-up systems are necessary. [19,23] Overall, the study supports a risk-adapted approach to prostate cancer diagnosis and management. PSA remains valuable for identifying men requiring further evaluation but should not be regarded as a definitive diagnostic test. mpMRI provides an important intermediate step between biochemical suspicion and biopsy, while targeted biopsy improves characterization of suspicious lesions. For appropriately selected men with low-risk disease, active surveillance offers an evidence-based strategy to reduce overtreatment while maintaining the opportunity for timely definitive intervention if progression occurs. [16,20,24]

The present study demonstrates that prostate cancer assessment is most effective when PSA testing is integrated with clinical examination, mpMRI, targeted biopsy, and histopathological risk stratification rather than using PSA alone as an indication for biopsy or treatment. In the constructed cohort, increasing PI-RADS category was associated with a greater likelihood of prostate cancer and clinically significant disease, supporting the role of mpMRI in guiding biopsy decisions. At the same time, the identification of low-grade disease highlights the importance of distinguishing clinically significant cancer from potentially indolent tumors. Active surveillance provided an appropriate management strategy for selected patients with favorable disease characteristics, potentially reducing unnecessary treatment-related morbidity while maintaining close monitoring for progression. Overall, a risk-adapted and patient-centered diagnostic pathway can help balance early detection of clinically significant prostate cancer against the risks of overdiagnosis, unnecessary biopsy, and overtreatment.

Recommendations

PSA-based assessment should be individualized according to age, symptoms, family history, PSA density, DRE findings, and overall clinical risk rather than relying on a single PSA threshold. Prostate mpMRI should be incorporated into the diagnostic pathway before biopsy whenever appropriate, with standardized PI-RADS reporting and MRI-targeted biopsy for suspicious lesions, supplemented by systematic sampling when clinically indicated. Patients with low-risk and carefully selected favorable intermediate-risk prostate cancer should be offered active surveillance when appropriate, supported by regular PSA monitoring, clinical assessment, repeat mpMRI, and biopsy according to predefined progression criteria. At Ayub Teaching Hospital, standardized multidisciplinary protocols involving urologists, radiologists, and histopathologists should be strengthened to improve diagnostic consistency and patient selection. Larger prospective multicenter studies with longer follow-up are recommended to validate these findings and determine the long-term outcomes, cost-effectiveness, and feasibility of MRI-based biopsy pathways and active surveillance in the Pakistani healthcare setting.