Clinical Findings

A. Symptoms
Most patients with early-stage CaP are asymptomatic. The presence of symptoms often suggests locally advanced or metastatic disease. Obstructive or irritative voiding complaints can result from local growth of the tumor into the urethra or bladder neck or from its direct extension into the trigone of the bladder. Metastatic disease to the bones may cause bone pain. Metastatic disease to the vertebral column with impingement on the spinal cord may be associated with symptoms of cord compression, including paresthesias and weakness of the lower extremities and urinary or fecal incontinence.

B. Signs
A physical examination, including a DRE, is needed. Induration, if detected, must alert the physician to the possibility of cancer and the need for further evaluation (ie, PSA, TRUS, and biopsy). Locally advanced disease with bulky regional lymphadenopathy may lead to lymphedema of the lower extremities. Specific signs of cord compression relate to the level of the compression and may include weakness or spasticity of the lower extremities and a hyperreflexic bulbocavernosus reflex.

C. Laboratory Findings
Azotemia can result from bilateral ureteral obstruction either from direct extension into the trigone or from retroperitoneal adenopathy. Anemia may be present in metastatic disease. Alkaline phosphatase may be elevated in the presence of bone metastases. Serum acid phosphatase may be elevated with disease outside the confines of the prostate.

D. Tumor Markers - Prostate-Specific Antigen (PSA)
Serum PSA has revolutionized our ability to detect CaP. Current detection strategies include the efficient use of the combination of DRE, serum PSA, and TRUS with systematic biopsy. Unfortunately, PSA is not specific for CaP, as other factors such as BPH, urethral instrumentation, and infection can cause elevations of serum PSA. Although the last two factors can usually be clinically ascertained, distinguishing between elevations of serum PSA resulting from BPH and those related to CaP remains the most problematic.

Numerous strategies to refine PSA for cancer detection have been explored. Their common goal is to decrease the number of false-positive test results. This would increase the specificity and positive predictive value of the test and lead to fewer unnecessary biopsies, lower costs, and reduced morbidity of cancer detection. Attempts at refining PSA have included PSA velocity (change of PSA over time), PSA density (standardizing levels in relation to the size of the prostate), age-adjusted PSA reference ranges (accounting for age-dependent prostate growth and occult prostatic disease), and PSA forms (free versus protein-bound molecular forms of PSA).

1. PSA velocity - PSA velocity refers to the rate of change of serum PSA. A retrospective study has shown that men with prostate cancer have a more rapidly rising serum PSA in the years before diagnosis than do men without prostate cancer. Patients whose serum PSA increases by 0.75 ng/mL/y appear to be at an increased risk of harboring cancer. However, PSA velocity must be interpreted with caution. An elevated PSA velocity should be considered significant only when several serum PSA assays are carried out by the same laboratory over a period of at least 18 months.

2. PSA density - PSA levels are elevated approximately 0.12 ng/mL per gram of BPH tissue. Thus, patients with enlarged glands due to BPH may have elevated PSA levels. The ratio of PSA to gland volume is termed the PSA density. Some investigators advocate prostate biopsy only if the PSA density exceeds 0.1 or 0.15, while others have not found PSA density to be useful. Problems with this approach include the facts that (1) epithelial-stromal ratios vary from gland to gland and only the epithelium produces PSA, and (2) errors in calculating prostatic volume may approach 25%. The positive predictive value of PSA density is slightly higher than the use of a PSA level > 4 ng/mL in several series (30-40% vs. 20-30%).

3. Age-adjusted reference ranges for PSA - Age-adjusted PSA values for normal men are presented in

Table 22-5 (Oesterling JE et al, 1993). It is thought that the rise in PSA with increasing age results from prostate gland growth from BPH, the higher incidence of subclinical prostatitis, and the growing prevalence of microscopic, clinically insignificant prostate cancers. Age-adjusted reference ranges increase the sensitivity in younger patients and increase the specificity in older patients. Concerns over the general applicability of these reference ranges have been raised because they were derived from US midwestern white men.

4. Racial variations in CaP detection - Although much evidence of racial variations in the incidence and mortality of CaP has been noted, little information is available on possible racial variations for cancer detection strategies. Recent reports have proposed different PSA density and age-specific reference ranges for African Americans and whites.

5. Molecular forms of PSA - The most recent refinement in PSA has been the recognition of the various molecular forms of PSA - free and protein-bound. Approximately 90% of the serum PSA is bound to alpha-1-antichymotrypsin, and lesser amounts are free or are bound to alpha-2-macroglobulins. In the latter form, no epitopes to the antibodies used in the current assays are available, while PSA bound to alpha-1-antichymotrypsin may have 3 of its 5 epitopes masked. Early studies suggest that prostate cancer patients demonstrate a lower percentage of free PSA than do patients with benign disease. A large multicenter study has reported that in men with a normal DRE and a total PSA level between 4 and 10 ng/mL, a 25% free PSA cutoff would detect 95% of cancers while avoiding 20% of unnecessary biopsies. The cancers associated with greater than 25% free PSA were more prevalent in older patients and generally were less threatening in terms of tumor grade and volume (Catalona et al, 1998). Further validation studies with definition of optimal cutoff levels for different assays are needed, and issues such as possible racial variations in these levels must be addressed.

E. Prostate Biopsy
Systematic sextant prostate biopsy was the most commonly employed technique used in detecting CaP. Biopsies are usually obtained under TRUS guidance, from the apex, midsection, and base of each side of the prostate at the midsagittal line halfway between the lateral border and midline of the gland (Hodge et al, 1989). Information from sextant biopsies has mainly focused on cancer detection and has been underutilized for cancer staging. Several investigators have demonstrated some utility of systematic sextant biopsies in predicting extracapsular extension and risk of relapse following radical prostatectomy.

Refinement in systematic biopsy strategies to increase cancer detection rates is ongoing. It is clear that more extensive biopsy schemes that sample the lateral aspect of the prostate increase cancer detection (Eskew et al, 1997; Presti et al, 2000). Such extended biopsy schemes are critical in patients undergoing repeat biopsy (Chon et al, 2002).

F. Imaging
1. TRUS - TRUS is useful in performing prostatic biopsies and in providing some useful local staging information if cancer is detected. Almost all prostate needle biopsies are performed under TRUS guidance. This allows uniform spatial separation and sampling of the regions of the prostate and also makes lesion-directed biopsies possible. If visible, CaP tends to appear as a hypoechoic lesion in the peripheral zone.

TRUS provides more accurate local staging than does DRE. The sonographic criteria for extracapsular extension are bulging of the prostate contour or angulated appearance of the lateral margin. The criteria for seminal vesicle invasion are a posterior bulge at the base of the seminal vesicle or asymmetry in echogenicity of the seminal vesicle associated with hypoechoic areas at the base of the prostate.

TRUS also enables measurement of the prostate volume, which is needed in the calculation of PSA density. Typically, a prolate ellipsoid formula is used: (π/6) × (anterior-posterior diameter) × (transverse diameter) × (sagittal diameter). TRUS is also used in the performance of cryosurgery and brachytherapy (see below).

2. Endorectal magnetic resonance imaging - The reported staging accuracy of endorectal coil magnetic resonance imaging (MRI) varies from 51% to 92%. While rendering high image quality, the endorectal coil MRI appears to be operator dependent, requiring education and expertise. Costs associated with endorectal MRI are also high, and until this methodology demonstrates superiority in providing clinical information that alters patient management, its use should be limited. Attempts to identify patients who could potentially benefit from this imaging are ongoing.

3. Axial imaging (CT, MRI) - Cross-sectional imaging of the pelvis in patients with CaP is selectively performed to exclude lymph node metastases in high-risk patients who are thought to be candidates for definitive local therapy, whether it be surgery or irradiation. Both MRI and computed tomography (CT) are used for this purpose. Patients identified as having lymphadenopathy on imaging may undergo CT-guided fine-needle aspiration. If lymph node metastases are confirmed, such patients may be candidates for alternative treatment regimens. However, the incidence of lymph node metastases in contemporary radical prostatectomy series is low (< 10%). In addition, imaging is costly and its sensitivity is limited (30-40%). Various criteria can be used to identify patients for axial imaging, including negative bone scans and either T3 cancers or a PSA > 20 ng/mL and primary Gleason grade 4 or 5 cancers.

Analyses of several contemporary series of patients with clinically localized prostate cancer suggest that the risk of lymph node metastases is low and that its risk can be quantified on the basis of serum PSA, local tumor stage, and tumor grade. The serum concentration of PSA correlates well with cancer volume and stage. However, considerable overlap exists, making the use of serum PSA alone inaccurate for clinical staging in most patients. Use of serum PSA in conjunction with tumor grade and stage adds considerable sensitivity and specificity to the prediction of lymph node status compared with the use of PSA alone. Several investigators have published nomograms and probability curves that aid in predicting pathologic stage (Partin et al, 1997; Narayan et al, 1995; Bostwick et al, 1996).

4. Bone scan - When prostate cancer metastasizes, it most commonly does so to the bone. Soft tissue metastases (eg, lung and liver) are rare at the time of initial presentation. Although a bone scan has been considered a standard part of the initial evaluation of men with newly diagnosed prostate cancer, good evidence has been accumulated that it can be excluded in most of these men on the basis of serum PSA. Oesterling and colleagues have conducted studies to assess the ability of serum PSA to predict bone scan findings (Oesterling JE et al, 1993). On the basis of their results, bone scans can be omitted in patients with newly diagnosed, untreated prostate cancer who are asymptomatic and have serum PSA concentrations < 10 ng/mL.

G. Molecular Staging
Molecular staging refers to the detection of circulating prostate cells in the peripheral blood of men with CaP. The application of reverse transcription-polymerase chain reaction (RT-PCR) uses peripheral blood samples and attempts to identify the presence of the messenger RNA to PSA. If detected, this is indirect evidence of prostate cells in the peripheral circulation. However, the clinical significance of positive RT-PCR test results at the present time is unknown. Numerous tumor systems have been identified that shed tumor cells into the circulation, but this finding is not always indicative of metastatic disease or treatment failure. Further studies are needed before the widespread application of this methodology.