PSA occurs in two major forms in the blood. One form is attached to blood proteins while the other circulates free (unattached). The percent-free PSA (fPSA) is the ratio of free PSA circulates compared to the total PSA level. Percent free PSA has been demonstrated to improve PSA usefulness both in the grey zone (PSA 4–10 ng/ml) and from 2.5 to 4 ng/ml [56]. The recommended cut-off to recommend prostate biopsies is 10 % or less, although men should be cautious if it is between 10 and 25 % as this is considered the grey zone. The major problem of free PSA is that its value is influenced by prostate volume and associated prostatitis. Furthermore, the cut-off of 25 % is far from being universally agreed upon.

PSA levels are higher in men with larger prostate glands [57]. The PSA density (PSAD) is sometimes used for men with large prostate glands to try to adjust for this observation. The classical cut-off is 0.15 ng/ml/cc. PSA density has not been shown to be as useful as the percent-free PSA test in clinical practice although it is integrated sometimes in risk calculators.

PSA adjusted for transition zone volume (PSA density of the transition zone) has been shown to be more accurate than the prostate-specific antigen density in distinguishing prostate cancer from benign prostatic hyperplasia in men with intermediate serum prostate-specific antigen of 4.1–10.0 ng/mL, from 2.5 to 4 ng/ml and in men with initial negative biopsies. Limitations to its widespread use include the variability of the transition zone measurement by TRUS [56, 58, 59].

PSA levels are normally higher in older men than in younger men, even when there is no cancer. This is because a major source of PSA leakage comes from the transition zone of the prostate which enlarges as men age. However, due to the usefulness of age-specific PSA ranges is not well proven, most authors do not recommend their use at this time outside of being integrated in risk calculators or nomograms.

PSA increases more rapidly in men with prostate cancer than in healthy men. The Baltimore Longitudinal Study of Aging (BLSA) found that men with a PSA rate of change (PSA velocity) greater than 0.75 ng/mL/year were at an increased risk of being diagnosed with prostate cancer and that PSA velocity was more specific than a 4.0 ng/mL PSA cutoff (90 versus 60 % specificity). The study results, though, were based on analyzing the banked serum of only 18 cancer cases, PSA velocity and its cut-off [60].

Data from the Rotterdam arm of the ERSPC trial found that PSA velocity was significantly higher in men with prostate cancer than in men with a negative biopsy (0.62 vs. 0.46 ng/mL/year). However, PSA velocity did not independently predict cancer after adjusting for PSA level [61].

Urologists are frequently faced with the dilemma of treating a patient with a high index of suspicion for prostate cancer, but with an initial set of negative biopsies. Negative biopsy does not ensure the absence of disease [62]. Whatever parameter is used to determine the need for a repeat biopsy, it is important to have a look at first the initial biopsy. Factors to consider include the location and number of cores taken as well as the size of the prostate.

If the prior negative biopsy was a sextant scheme, the cancer detection rate may be as high as 39 % with a repeat extended biopsy, whereas if the prior negative biopsy was an extended scheme, the cancer detection rate is usually much lower between 15 and 30 %. Saturation biopsy techniques and transperineal templates have also been proposed but supplanted nowadays by imaging techniques like MRI [34]. The variability in cancer detection rates does not justify its invasiveness (Table 40.1). Others have proposed up to 21 biopsies in previously negative biopsies [63].

Post-radiotherapy (RT) prostate biopsies are likely to pose problems in histological interpretation. False negatives due to sampling error, false positives due to delayed tumour regression, and indeterminate biopsies showing radiation effect in residual tumour of uncertain viability are common occurrences [64]. However, with very experienced uro-pathologists, these limitations can be minimized.

The main aims of the TRUS biopsy are not only to diagnose prostate cancer but also to determine its aggressiveness. This is especially true at a time of increased complication risks after TRUS biopsies and with the dilemma posed by low volume, low grade prostate cancer. Nomograms are often used to predict the likelihood of a positive biopsy and several have now incorporated more extended biopsy schemes in their calculations, including for repeat biopsies [65].

Transrectal ultrasound (TRUS)–guided biopsy is the preferred method except in patients who had the rectum and anus excised, in which case the biopsy is performed by the transperineal route. TRUS is carried out by using a 5- to 8-MHz handheld high-resolution probe with capabilities of sagittal and transverse (coronal) imaging (Fig. 40.1). A disposable adaptor is fitted on the probe that will direct the biopsy needle into various regions of the prostate as guided by ultrasound imaging. Currently, extended schemes consisting of at least 10–12 biopsies including lateral biopsies, but without transition zone biopsy, is now considered as the diagnostic gold standard (Fig. 40.2). Some authors have argued that more extended schemes minimize the risk of missing an aggressive disease but this remains debated [66]. Extended schemes decrease the grade discordance between biopsy and prostatectomy specimens but increase the risk of detecting insignificant prostate cancer.

Transrectal guided prostate biopsy is not without risks and complications. Taking more biopsy cores does not necessarily increase the complication rates [72]. Most of the following complications are minor and self-limiting but can cause considerable anxiety to the patients. Bleeding: urethral bleeding/hematuria (35 %), hematochezia (9 %), and hematospermia (5 %) are usually self-limiting and do not need any active treatment. Infections: prostatitis, epididymitis, and septicemia; sepsis is the most dangerous complication as it can be life-threatening in elderly patients. Outflow symptoms: painful micturition. Urine should be tested for infection and appropriate antibiotics usually improve symptoms. Urinary retention could be precipitated by the biopsy due to hemorrhage and edema. Catheterization is done to relieve the obstruction and a trial removal can be done a couple of days later.

Prostate cancer spreads locally within its zones and into the ejaculatory ducts, seminal vesicles, and neurovascular bundles. Distal spread includes lymphatic (to internal iliac lymph nodes) and hematogenous routes to bones, lungs, and other organs. The bony metastasis involves bones of the axial skeleton. Visceral metastasis is rarely seen in newly diagnosed patients and rarely seen even in patients dying of prostate cancer [73].

For clinical staging the extent of the prostate cancer is assessed by DRE, PSA, TRUS, and Gleason histological grading. For example, in patients with stage T1c or less disease with a total Gleason Score of 6 and a PSA of less than 10 ng/mL, no further staging investigations would be required unless there is a specific indication, like symptoms [74]. Selective cross-sectional imaging modalities like computed tomography (CT), MRI and bone scan help to assess the extent of spread and are mainly performed for the following reasons:

The risk of metastasis can be quantified by PSA levels, number of positive cores and clinical and TRUS biopsy findings. Noteworthy, in contemporary patients with PCa, the accuracy of CT scan as a preoperative nodal-staging procedure is poor, even in patients with high risk of lymph node involvement [75].