Benign and malignant changes in the prostate increase with age. Autopsies of men in the eighth decade of life show hyperplastic changes in >90% and malignant changes in >70% of individuals. The high prevalence of these diseases among the elderly, who often have competing causes of morbidity and mortality, mandates a risk-adapted approach to diagnosis and treatment. This can be achieved by considering these diseases as a series of states. Each state represents a distinct clinical milestone for which therapy(ies) may be recommended based on current symptoms, the risk of developing symptoms, or death from disease in relation to death from other causes within a given time frame (Fig. 95-1). For benign proliferative disorders, symptoms of urinary frequency, infection, and potential for obstruction are weighed against the side effects and complications of medical or surgical intervention. For prostate malignancies, the risks of developing the disease, symptoms, or death from cancer are balanced against the morbidities of the recommended treatments and preexisting comorbidities.
Clinical states of prostate cancer. PSA, prostate-specific antigen.
The prostate is located in the pelvis and is surrounded by the rectum, the bladder, the periprostatic and dorsal vein complexes and neurovascular bundles that are responsible for erectile function, and the urinary sphincter that is responsible for passive urinary control. The prostate is composed of branching tubuloalveolar glands arranged in lobules surrounded by fibromuscular stroma. The acinar unit includes an epithelial compartment made up of epithelial, basal, and neuroendocrine cells and separated by a basement membrane, a stromal compartment that includes fibroblasts and smooth-muscle cells. Prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) are produced in the epithelial cells. Both prostate epithelial cells and stromal cells express androgen receptors (ARs) and depend on androgens for growth. Testosterone, the major circulating androgen, is converted by the enzyme5α-reductase to dihydrotestosterone in the gland.
The periurethral portion of the gland increases in size during puberty and after the age of 55 years due to the growth of nonmalignant cells in the transition zone of the prostate that surrounds the urethra. Most cancers develop in the peripheral zone, and cancers in this location can often be palpated during a digital rectal examination (DRE).
In 2010 approximately 217,730 prostate cancer cases were diagnosed, and 32,050 men died from prostate cancer in the United States. The absolute number of prostate cancer deaths has decreased in the past 5 years, which has been attributed by some to the widespread use of PSA-based detection strategies. However, the benefit of screening on survival is unclear. The paradox of management is that although 1 in 6 men will eventually be diagnosed with the disease, and the disease remains the second leading cause of cancer deaths in men, only 1 man in 30 with prostate cancer will die of his disease.
Epidemiologic studies show that the risk of being diagnosed with prostate cancer increases by a factor of two if one first-degree relative is affected and by four if two or more are affected. Current estimates are that 40% of early-onset and 5–10% of all prostate cancers are hereditary. Prostate cancer affects ethnic groups differently. Matched for age, African-American males compared to white males have both a greater number of typically multifocal and highly unstable prostatic intraepithelial neoplasia (PIN) lesions, which are precursors to cancer, and larger tumors, possibly related to the higher levels of testosterone seen in African American males. Polymorphic variants of the AR, the cytochrome P450 C17, and the steroid 5α-reductase type II (SRD5A2) genes have also been implicated in the variations in incidence.
The prevalence of autopsy-detected cancers is similar around the world, while the incidence of clinical disease varies. Thus, environmental factors may play a role. High consumption of dietary fats, such as α-linoleic acid, or the polycyclic aromatic hydrocarbons that form when red meats are cooked is believed to increase risk. Similar to breast cancer in Asian women, the risk of prostate cancer in Asian men increases when they move to Western environments. Protective factors include consumption of the isoflavonoid genistein (which inhibits 5α-reductase) found in many legumes, cruciferous vegetables that contain the isothiocyanate sulforaphane, retinoids such as lycopene found in tomatoes, and inhibitors of cholesterol biosynthesis (e.g., statin drugs). The development of prostate cancer is a multistep process. One early change is hypermethylation of the GSTP1 gene promoter, which leads to loss of function of a gene that detoxifies carcinogens. The finding that many prostate cancers develop adjacent to a lesion termed PIA (proliferative inflammatory atrophy) suggests a role for inflammation.
Diagnosis and Treatment by Clinical State
The prostate cancer continuum—from the appearance of a preneoplastic and invasive lesion localized to the prostate, to a metastatic lesion that results in symptoms and, ultimately, mortality—can span decades. To facilitate disease management, competing risks are considered in the context of a series of clinical states (Fig. 95-1). The states are defined operationally on the basis of whether or not a cancer diagnosis has been established and, for those with a diagnosis, whether or not metastases are detectable on imaging studies and the measured level of testosterone in the blood. With this approach, an individual resides in only one state and remains in that state until he has progressed. At each assessment, the decision to offer treatment and the specific form of treatment is based on the risk posed by the cancer relative to competing causes of mortality that may be present in that individual. It follows that the more advanced the disease, the greater the need for treatment.
For those without a cancer diagnosis, the decision to undergo testing to detect a cancer is based on the individual's estimated life expectancy and, separately, the probability that ...