Pathophysiology
Biology Of Prostate Cancer.
The development and maintenance of the normal adult prostate are under the hormonal control of androgens acting through the androgen receptor (AR). The androgens are converted to testosterone in peripheral tissues and the prostate gland. Testosterone diffuses into the epithelial or stromal cells, where it is converted into the functionally active androgen dihydrotestosterone (DHT) by the action of the 5-alpha (- α) reductase enzyme system located on the nuclear membrane. DHT binds to the androgen receptor, which undergoes a conformational change and is transported into the nucleus. Inside the nucleus of the cell, the androgen receptor (which is bound to DHT) binds to the target genes and initiates transcription. In this way, the androgen receptor ultimately controls the regulation of the cell cycle, cell growth, and cell differentiation.
Prostate-Specific Antigen.
Prostate-specific antigen (PSA) is a protein produced in the epithelial cells of the prostate. In men younger than age 40, small amounts of PSA (less than 4 ng / mL) circulate in the blood; these levels rise naturally with age, corresponding to an age-dependent increase in prostate size. In general, the higher the PSA level in the bloodstream, the greater the chance of developing CaP. However, some men with CaP do not have high PSA levels, and two-thirds of men with elevated levels of PSA do not have CaP. High PSA levels may also indicate nonmalignant conditions, such as benign prostatic hyperplasia. Indeed, it has been suggested that PSA population screening could result in men making the wrong decision and having unnecessary, aggressive treatment. In practice, many clinicians believe that PSA velocity or doubling time is more significant than the absolute PSA level for determining the aggressiveness of the tumor. A recent study found that men with high-risk early-stage CaP (as defined by high PSA velocity) have a high risk of death from CaP despite radical prostatectomy.
Recent findings from a population-based, case-controlled study reported at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2004 suggest that PSA screening among asymptomatic men may substantially reduce the risk of metastatic CaP. Further research is needed to confirm these results in a randomized trial. A comparison study found that PSA screening of men at ages 40 and 45, then every two years beginning at age 50, would save more lives than the current model—annual screening beginning at age 50. The former schedule prevented 3.3 deaths and involved an additional 7,500 tests and 450 prostate biopsies. The standard strategy (annual PSA testing beginning at age 50) prevented 3.2 deaths but required an additional 10,500 tests and 600 biopsies. Researchers based these estimates on a PSA level of 4.0 ng / mL for prostate biopsy. The earlier, less frequent schedule would save money and reduce the number of unnecessary biopsies performed each year. The study was primarily in white populations; consequently, these results may not apply to men of other races.
Key applications of PSA as a tumor marker include the following:
• Screening of the general male population. Although widespread, ad hoc screening has clearly resulted in a shift toward the detection of earlier cancers, no prospective, controlled studies of PSA screening have shown that PSA measurement reduces morbidity or mortality.
• Monitoring response to treatment. Failure to achieve PSA of close to 0 ng / mL after local treatment suggests that metastatic disease is already present.
• Detecting recurrence. A rise in PSA from initially low levels achieved following local treatment such as radiotherapy or radical prostatectomy (RP) likely reflects a recurrence of the tumor. The availability of the PSA test to detect recurrence (unique among solid tumors) has engendered a huge shift toward early treatment; patients are increasingly treated upon PSA rise rather than waiting several years until metastases are visible on imaging studies.
• Evaluation of response to novel therapies. The PSA Working Group has recommended a standardized method for reporting PSA response in Phase II trials: trials should report a decline of 50% or greater, versus less than 50%. The group based this standard on the findings of several small trials that statistically associated a 50% or greater decline with improved survival.
Research is ongoing to enhance the sensitivity of PSA testing by using one of the following markers as an adjunct:
• Human glandular kallikrein-2.
• Insulin growth factor-1.
• Binding protein-3.
Staging.
In common with most cancers, prostate tumors are staged according to their degree of metastasis. The most commonly used staging scheme is the primary tumor, regional lymph node, and distant metastases (TNM) system, which is replacing the older Jewett-Whitmore system. Table 1 describes the TNM system in detail.
The American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) adopted the revised TNM staging system in 1992. This system was revised again in 1997 to include reference to tumor grade (the degree of abnormality of cancer cells compared with normal cells). The TNM system now uses broad tumor stage categories, including a stage to describe patients whose only sign of CaP is an abnormal PSA level, and assigns cancers to stages I through IV. TNM was further revised in 2002 to include new T subcategories of prostate tumors for cancer cases diagnosed from January 2003. Figure 1 shows the timescale for CaP’s progression through the disease stages.
TABLE 1. TNM Staging Classification System for Prostate Cancer
| Primary Tumor | Regional Lymph Nodes | Distant Metastasis | Histopathological Grade | AJCC / UICC (1992) Stage | AJCC / UICC (1997) Stage | AJCC (2002) Stage |
| T1a | NO | MO | G1 | I | I | I |
| T1a | NO | MO | G2, 3-4 | I | II | |
| T1b | NO | MO | Any G | I | II | |
| Tie | NO | MO | Any G | I | II | |
| T1 | NO | MO | Any G | II | ||
| T2 | NO | MO | Any G | II | II | |
| T2a | NO | MO | Any G | II | II | |
| T2b | NO | MO | Any G | II | II | |
| T3 | NO | MO | Any G | III | III | III |
| T4 | NO | MO | Any G | IV | IV | IV |
| AnyT | N1 | MO | Any G | IV | IV | IV |
| AnyT | Any N | M1 | Any G | IV | IV | IV |
TNM = Tumor, node, and metastasis.
Grading.
Histologically, nearly all CaP are adenocarcinomas, which are further classified by grade. The Gleason scoring system (the most commonly used measure for grading CaP) recognizes that CaP is a multifocal disease with heterogeneous distribution within the gland. Thus, two individual scores, each ranging from 1 to 5, are given to the two most predominant histological patterns of CaP in a biopsy sample. The two scores are added together to give the Gleason sum. In the 1997 AJCC cancer staging manual, sums of 2-4 represent well-differentiated disease; 5-7, moderately differentiated disease; and 8-10, poorly differentiated disease. This system is slightly different in the 2002 edition, in which sums of 5-6 represent moderately differentiated disease and 7-10, poorly differentiated disease. However, the Gleason score is emphasized as the grading system of choice, not the definitions of the scores.
Physicians collect the sample via a needle biopsy of the prostate, and the scores are based on morphological appearances corresponding to the size and pattern of the tumor. The Gleason score can help predict the chance of cancer spread. For example, published reports indicate risk of lymph node metastasis in the range of 2%, 13%, and 23% for patients with Gleason scores of five, six, and eight, respectively. Gleason scores based on samples taken after radical prostatectomy, rather than on needle biopsy samples, are more accurate and precise; these postprostatectomy samples are assigned Gleason scores to aid in decisions about adjuvant therapy (usually radiation).
FIGURE. Prostate cancer disease progression.
Bone Metastases.
The skeleton is the major site of CaP metastases. Approximately 70% of CaP metastases involve the skeleton, and the major cause of hospitalization of CaP patients is for the relief of bone pain. CaP usually forms osteosclerotic lesions characterized by increased osteolysis (bone destruction) and increased bone formation (osteogenesis) around tumor deposits. Osteolytic metastases can cause severe pain, pathological fractures, life-threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. Growth factors potentially involved in increased bone formation include transforming growth factor-beta-2, basic fibroblast growth factors-1 and -2, bone morphogenetic protein, PSA, and endothelin-1. A recent study found that patients with PSA 20 ng / mL or greater, locally advanced disease (T3 and T4), or Gleason score eight or higher are at high risk for bone metastases; such patients should therefore be considered for bone scan. Agents that block bone resorption such as the bisphosphonates ease bone pain, spinal cord compression, and the risk of pathological fractures. Bisphosphonates are not covered here because of their lack of direct antitumor effect in CaP; these agents are used only for symptom relief.
TABLE 2. Combined-Modality Risk Stratification for Prostate Cancer
| Risk Group | Diagnostic Markers |
| Low risk | PSA <10 ng / mL and biopsy Gleason score <6 and AJCCTIc orT2a |
| Intermediate risk | PSA > 10-20 ng / mL or biopsy Gleason score of 7 or AJCC T2b |
| High risk | PSA >20 ng / mL or biopsy Gleason score of 8-10 or bilateral disease |
AJCC = American Joint Committee on Cancer; PSA = Prostate-specific antigen.
Prognostic Factors.
The probability that an apparently early-stage CaP will recur after local therapy depends on the three most important clinical prognostic factors: the clinical stage of the cancer, its grade, and the PSA level before treatment. Preoperative or postoperative nomograms or “Partin tables” have been developed for localized cancers. These tables combine clinical stage, Gleason score, preoperative PSA levels, surgical margin status, lymph node status, and prostatic cap invasion to aid physicians in evaluating prognosis. Table 2 shows how PSA stage, AJCC stage, and Gleason score can be combined to stratify risk.
When the cancer is confined to the prostate gland (stages I or II), median survival is likely to exceed five years. Patients with locally advanced cancer (stage III) usually are not curable, and most will eventually die of their tumor, although median survival may be as long as five to seven years. If CaP has spread to distant organs (metastatic stage IV disease), current therapies will not cure it, and median survival is usually one to three years. However, even in this last group of patients, some cancers spread slowly and the patient lives for many years with the disease. This scenario highlights the need for better prognostic indicators.
In the 1997 AJCC cancer staging manual, poorly differentiated (Gleason score of eight or more) tumors are more likely to have metastasized by the time they are diagnosed and are associated with a worse prognosis. Furthermore, in the majority of studies, flow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-specific survival in some CaP patients. Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors.
Among patients with hormone-refractory CaP, factors affecting prognosis include performance status, hemoglobin level, and serum levels of lactate dehy-drogenase and alkaline phosphatase.
Potential new markers predictive of early relapse (for testing tumor samples after radical prostatectomy) include the following:
• E-cadherin
• Microvessel density
• Ki-67 proliferation index
• Neuroendocrine differentiation
• Bcl-2 status
. HER2 status
. CDK1
• Caveolin-1
. P27
. TGF
In each case, more studies are needed because available evidence of the predictive power of these markers is either conflicting or preliminary.