Prostate Cancer - Pathophysiology and Natural History (part3)
Pathophysiology
Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most prostate cancers are adenocarcinomas (95%).
Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. Few cases have neuroendocrine morphology. When present, they are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.
Of cases of prostate cancer, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.
Natural history
The natural history is still relatively unknown, and many aspects of progression are poorly understood. Symptoms or abnormal DRE findings in the pre-PSA era only brought 40-50% of patients with prostate cancer to medical attention, and these patients usually had locally advanced disease. The advent of PSA testing has helped identify patients with less-advanced, organ-confined disease.
Evidence suggests that most prostate cancers are multifocal and heterogeneous. Cancers can start in the transitional zone or, more commonly, the peripheral zone. When these cancers are locally invasive, the transitional zone tumors spread to the bladder neck, while the peripheral zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces is a relatively late event.
The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, occasionally without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread, the mechanical theory and the seed-and-soil theory.
The mechanical theory involves direct spread through the lymphatics and venous spaces into the lower lumbar spine. Advocates of the seed-and-soil theory believe tissue factors must be present that allow for preferential growth in certain tissues, such as the bone. Lung, liver, and adrenal metastases have also been documented. Specific tissue growth factors and extracellular matrices are possible examples.
The doubling time in early-stage disease is as slow as 2-4 years, but this changes as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.
Taken together, these data suggest that although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. In addition, these findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.
Prostate Cancer - Pathophysiology and Natural History
© eMedicine
Tags: Cancer, Pathophysiology, Prostate