Prostate Cancer

Epidemiology

Prostate cancer is the most common nonskin cancer that affects U.S. men, with approximately 270,000 new cases diagnosed annually and approximately 35,000 deaths each year. Worldwide, approximately 1.4 million cases of prostate cancer are diagnosed annually and lead to approximately 375,000 deaths each year. The disease is the most common cancer among men in much of Europe, North America, and Australia, but lower rates are observed in Asia. Higher mortality rates are observed in sub-Saharan Africa and the Caribbean, likely because of much lower rates of early detection.

In developed countries, the widespread use of screening with prostate-specific antigen (PSA) testing, beginning in the early 1990s, led to a rapid increase in the reported annual incidence of prostate cancer, mostly attributable to the identification of asymptomatic cases. Since 1992, however, the reported incidence rate of prostate cancer has fallen by 50%, first because of an acceleration of diagnosis for early prevalent cases and subsequently because of more conservative recommendations regarding PSA screening.

The three well-recognized risk factors for prostate cancer are advanced age, ethnicity, and family history. Prostate cancer is rarely diagnosed before age 40 years, and the average age of onset is approximately age 68 years. In the United States, non-Hispanic Black men have the highest incidence of prostate cancer (171.6 cases/100,000 population age adjusted) and the highest mortality (38.3/100,000) from the disease. In contrast, Asian/Pacific Islander men have the lowest incidence and mortality (53.8/100,000 and 8.8/100,000, respectively). About 10% of all prostate cancers in the United States are early onset, diagnosed at or before age 56 years; such men are more likely have a genetic component to their disease. The risk of prostate cancer is related to the number of affected family members, regardless of whether the first-degree relatives are affected, and the presence of early-onset disease in the pedigree. Familial clustering of prostate cancer appears to be related to genetic factors, with no evidence that shared environment contributes to familial clustering. Other possible risk factors include high consumption of dietary fats, high intake of calcium, exposure to dioxin, and prior prostatitis.

Pathobiology

Most prostate cancers are adenocarcinomas and arise from the epithelial cells that line the prostate gland. Prostate-specific antigen (PSA) is an androgen-regulated serine protease that is produced by epithelial cells in the prostate gland as well as by cancers that arise from these cells. High grade prostatic intraepithelial neoplasia and atypical small acinar proliferation are precursor lesions.

The PTEN protein is commonly lost in aggressive prostate cancers, generally through genomic deletion. Transposition of the transmembrane protease gene TMPRSS2 to the ETS family member ERG gene, thereby creating the TMPRSS2-ERG fusion, is seen in 40 to 50% of prostate cancers, especially in White men. Other molecular abnormalities that are seen in cases without an ETS gene fusion include: overexpression of the serine peptidase gene SPINK1 ; recurrent point mutations in the transcriptional repressor gene SPOP ; loss and/or mutations in the CHD1 gene; and alterations in members of the RAS/RAF gene family. Metastatic and/or castrate-resistant prostate cancers often have aberrations in the androgen receptor, TP53 , and RB1 genes in addition to loss of PTEN.

Rare nonsynonymous mutations in the transcription factor HOXB13 are associated with a three- to four-fold increased risk of prostate cancer. Prostate cancer is also increased in carriers of BRCA1 and BRCA2 mutations. About 12% of men with metastatic prostate cancer have a germline mutation in a DNA repair gene.

Histologies other than adenocarcinomas are reported in less than 5% of cases. Ductal and intraductal cancers may be related to germline DNA repair gene mutations.

Clinical Manifestations

In the United States and most developed countries, the majority of men who are diagnosed with prostate cancer are asymptomatic and have tumors that are discovered by PSA screening. Men who have localized disease may complain of a variety of lower urinary tract symptoms, including urinary retention, frequency, and nocturia. Other symptoms may include hematuria and hematospermia. For men who present with metastatic disease, symptoms may include fatigue, weight loss, and bone pain. Spinal cord compression ( Chapters 164 and 175 ) can be heralded by increasing and well-localized back pain that is associated with weakness and urinary retention. Some men with locally advanced prostate cancer may present with edema, hypertension, and renal failure. At the time of diagnosis, about 75% of men will have localized disease, about 15% will have regional disease, and about 10% will have distant disease.

Diagnosis

An elevated PSA level is a nearly universal finding in patients who have prostate cancer. However, an elevated PSA level can be caused by many noncancerous conditions including benign prostatic hypertrophy and prostatitis ( Chapter 114 ). Most men undergo transrectal ultrasound-guided biopsy of the prostate gland to diagnose prostate cancer, but biopsy guided by magnetic resonance imaging (MRI) can improve the accuracy of the biopsy. Since prostate cancer is often multifocal, usually 10 to 12 cores are obtained , but MRI-directed targeted biopsies of suspicious areas alone are an alternative. Infection is a risk of the procedure, and antibiotic prophylaxis (e.g., a single 750 mg oral dose of ciprofloxacin or a single 160/800 mg oral dose of trimethoprim/sulfamethoxazole) is standard before the procedure. A routine urine culture can be obtained before the procedure to guide prophylactic prebiopsy and postbiopsy treatment if bacteria are detected ( Chapter 263 ). Since bleeding is another procedural risk, anticoagulant and/or antiplatelet medications are ideally discontinued for the procedure and restarted afterwards.

Prostate cancers are graded by their Gleason score ( Table 186-1 ), which grades the histology of the most frequent patterns on biopsy and then sums the two scores.

Atypical small acinar proliferation is observed in approximately 5% of prostate biopsies, and between 30 to 50% of individuals with this finding will have invasive cancer on repeat biopsy. Men whose biopsies show high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation are generally reevaluated at 6- to 24-month intervals and should be considered for biomarker tests or imaging to aid in cancer diagnosis if appropriate. Benign findings on a prostate biopsy include atrophy, adenosis, atypical adenomatous hyperplasia, and acute or chronic inflammation.

Treatment