• Androgens are of central importance. Cancer of the prostate does not develop in males who are castrated before puberty, indicating that androgens somehow provide the “soil,” the cellular context, within which prostate cancer develops. This dependence on androgens extends to established cancers, which often regress for a time in response to surgical or chemical castration. Notably, tumors that are resistant to anti-androgen therapy often acquire androgen receptor gene amplifications or mutations that permit androgen receptors to activate the expression of their target genes despite therapy. Thus, tumors that recur in the face of anti-androgen therapies still depend on gene products regulated by androgen receptors for their growth and survival. However, while prostate cancer, like normal prostate, is dependent on androgens for its survival, there is no evidence that androgens initiate carcinogenesis, nor are androgen levels associated with prostate cancer risk.
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Heredity also contributes, as there is an increased risk among first-degree relatives of patients with prostate cancer. Prostate cancer is uncommon in Asians and its incidence is highest among African-Americans and in Scandinavian countries. Aggressive, clinically significant disease is more common in African-Americans than in Caucasians. Genome-wide association studies have identified a number of genetic variants that are associated with increased risk for developing prostate cancer. Although each variant carries only a small increased risk, the effect is multiplicative, such that men with multiple risk alleles may have up to a 5-fold increase in risk compared to the general population.
Environment also plays a role, as evidenced by the fact that in Japanese immigrants to the United States the incidence of the disease rises (although not to the level seen in native-born Americans). Also, as the diet in Asia becomes more westernized, the incidence of clinically significant prostate cancer in this region of the world is increasing. However, the relationship between specific dietary components and prostate cancer risk is unclear.
• Acquired genetic aberrations, as in other cancers, are the actual drivers of cellular transformation. Copy number variations in specific chromosomal regions and gene rearrangements are frequently seen in primary tumors. The most common gene rearrangements in prostate cancer create fusion genes consisting of the androgen-regulated promoter of the TMPRSS2 gene and the coding sequence of ETS family transcription factors. TMPRSS2-ETS fusion genes are found in approximately 40% to 60% of prostate cancers in Caucasian populations, and they occur relatively early in tumorigenesis. Notably, the prevalence of these rearrangements is lower among African-Americans and other ethnic groups. Other mutations commonly lead to activation of the PI3K/AKT signaling pathway (Chapter 6); of these, the most common are loss-of-function mutations involving the tumor suppressor PTEN, which acts as a brake on PI3K activity.
MORPHOLOGYCarcinomasdetectedclinicallyareusuallynotvisiblegrossly.Moreadvancedlesionsappearasfirm,gray-whitelesionswithill-definedmarginsthatinfiltratetheadjacentgland(
Fig.18.13
Mostprostatecancersaremoderately differentiated adenocarcinomas thatproducewell-definedglands.Theglandstypicallyaresmallerthanbenignglandsandarelinedbyasingleuniformlayerofcuboidalorlowcolumnarepithelium,lackingthebasalcelllayerseeninbenignglands.Infurthercontrastwithbenignglands,malignantglandsarecrowdedtogetherandcharacteristicallylackbranchingandpapillaryinfolding.Thecytoplasmofthetumorcellsrangesfrompale-clear(asinbenignglands)toadistinctiveamphophilic(darkpurple)appearance.Nucleiareenlargedandoftencontainoneormoreprominentnucleoli(
Fig.