Prostate Cancer

Updated: Jan 30, 2017
  • Author: Gerald W Chodak, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Overview

Practice Essentials

Prostate cancer is the most common noncutaneous cancer in men in the United States. An estimated one in six white men and one in five African-American men will be diagnosed with prostate cancer in their lifetime, with the likelihood increasing with age.

The image below depicts the anatomy of the male pelvis and genitourinary tract.

Management of localized prostate cancer. This diag Management of localized prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.

See Prostate Cancer: Diagnosis and Staging, a Critical Images slideshow, to help determine the best diagnostic approach for this potentially deadly disease.

See Advanced Prostate Cancer: Signs of Metastatic Disease, a Critical Images slideshow, for help identifying the signs of metastatic disease.

Signs and symptoms

Currently, most cases of prostate cancer are identified by screening in asymptomatic men. Symptoms of prostate cancer include the following:

  • Urinary complaints or retention
  • Back pain
  • Hematuria

However, such symptoms are often from diseases other than prostate cancer (eg, urinary complaints from benign prostatic hyperplasia [BPH]). Physical examination alone cannot reliably differentiate benign prostatic disease from cancer.

Findings in patients with advanced disease may include the following:

  • Cancer cachexia
  • Bony tenderness
  • Lower-extremity lymphedema or deep venous thrombosis
  • Adenopathy
  • Overdistended bladder due to outlet obstruction

See Presentation for more detail.

Diagnosis

Elevated prostate-specific antigen (PSA) level

  • No PSA level guarantees the absence of prostate cancer.
  • The risk of disease increases as the PSA level increases, from about 8% with PSA levels of ≤1.0 ng/mL [1] to about 25% with PSA levels of 4-10 ng/mL and over 50% for levels over 10 ng/mL [1]

Abnormal digital rectal examination (DRE) findings

  • DRE is examiner-dependent, and serial examinations over time are best
  • Most patients diagnosed with prostate cancer have normal DRE results but abnormal PSA readings

Biopsy

  • Biopsy establishes the diagnosis
  • False-negative results often occur, so multiple biopsies may be needed before prostate cancer is detected

Screening

The American Cancer Society (ACS) recommends that men decide whether to be screened for prostate cancer based on a discussion with their health care provider about the uncertainties, risks, and potential benefits of screening. [2]

The recommended age for starting screening is as follows:

  • 50 years of age for men at average risk who have at least a 10-year life expectancy
  • 40 or 45 years of age for African Americans and men who have had a first-degree relative diagnosed with prostate cancer before age 65 years
  • 40 years of age for men with several first-degree relatives who had prostate cancer at an early age

The US Preventive Services Task Force (USPSTF) recommends against any routine PSA-based screening for prostate cancer. [3] This recommendation is considered controversial. [4]

See Workup for more detail.

Management

Localized prostate cancer

Standard treatments for clinically localized prostate cancer include the following:

  • Radical prostatectomy
  • Radiation therapy
  • Active surveillance
  • Androgen deprivation therapy (ADT)

Metastatic prostate cancer

Metastatic prostate cancer is rarely curable, and management of these cases typically involves the following:

  • Therapy directed at relief of particular symptoms (eg, palliation of pain)
  • Attempts to slow further progression of disease

See Treatment and Medication for more detail.

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Background

Prostate cancer is the most common noncutaneous cancer in men. Although prostate cancer can be a slow-growing cancer, thousands of men die of the disease each year. It is the second most common cause of cancer death in males (see Epidemiology).

Marked variation in rates of prostate cancer among populations in different parts of the world suggests the involvement of genetic factors. Familial predisposition also occurs. Environmental factors, notably diet, are also important (see Etiology).

Currently, the majority of prostate cancers are identified in patients who are asymptomatic. Diagnosis in such cases is based on abnormalities in a screening prostate-specific antigen (PSA) level or findings on digital rectal examination (see Presentation and Workup).

Screening for prostate cancer is a controversial topic, in large part because of the conflicting findings from prospective, randomized studies (see Workup). Education about the risks and benefits is important to help men make informed decisions regarding screening and, in those diagnosed with prostate cancer, the various treatment options (see Treatment). (See the image below.)

The standard approach for grading prostate cancer The standard approach for grading prostate cancer depends on a Gleason score, which is based on pathologic evaluation of a prostatectomy specimen and is commonly estimated from prostate biopsy tissue. Prostate cancer patterns are assigned a number from 1-5; the score is created by adding the most common pattern and the highest-grade patterns. Courtesy of Wikimedia Commons.

See also the following Medscape articles:

  • Precancerous Lesions of the Prostate
  • Prostate Cancer Diagnosis and Staging
  • Metastatic and Advanced Prostate Cancer
  • Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer
  • Prostate Cancer and Nutrition
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Anatomy

The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. (See the image below.)

Management of localized prostate cancer. This diag Management of localized prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.

The inferior vesical artery, which is derived from the internal iliac artery, supplies blood to the base of the bladder and prostate. The capsular branches of the inferior vesical artery help to identify the pelvic plexus arising from the S2-4 and T10-12 nerve roots. The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function.

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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 (95%) are adenocarcinomas.

Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. The few cases that have neuroendocrine morphology are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.

Squamous cell carcinomas constitute less than 1% of all prostate carcinomas. In many cases, prostate carcinomas with squamous differentiation arise after radiation or hormone treatment.

Of prostate cancer cases, 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.

Local spread and metastasis

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 occurs relatively late.

The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, often without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread: the mechanical theory and the seed-and-soil theory.

The mechanical theory attributes metastasis to direct spread through the lymphatics and venous spaces into the lower lumbar spine. Advocates of the seed-and-soil theory, however, believe that tissue factors that allow for preferential growth in certain tissues, such as bone, must be present. 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 variable. In the majority of cases, doubling time is longer than 4 years. Only a small percentage of prostate cancers double in less than 2 years. Doubling time tends to accelerate as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.

The natural history of clinically localized disease varies, with lower-grade tumors having a more indolent course and some high-grade lesions progressing to metastatic disease with relative rapidity. Given the typically slow progression of localized disease, several studies have examined the strategy of active surveillance in selected groups of patients. [5]

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Etiology

Marked variation in rates of prostate cancer among populations in different parts of the world suggests the involvement of genetic factors. For example, the risk of prostate cancer is particularly high in people of sub-Saharan African ancestry, while the risk tends to be low in many Asian populations. Increased risk in Asians who have migrated to the United States suggests the importance of environmental factors, notably diet. [6] Familial predisposition also occurs.

Prostate cancer is also found during autopsies performed in men with other causes of death. The rate of this latent or autopsy cancer is much greater than that of clinical cancer. In fact, it may be as high as 80% by age 80 years. Interestingly, the prevalence of the latent or autopsy form of the disease is similar worldwide. Together with migration studies, this suggests that environmental factors play a significant promoting role in the development of a clinical cancer from a latent precursor.

Genetics

Studies in different populations have identified several variants in the 8q24 region on chromosome 8 that are associated with increased risk of prostate cancer. [7] Gene alterations on chromosome 1, chromosome 17, and the X chromosome have been found in some patients with a family history of prostate cancer. The HPC1 (hereditary prostate cancer 1) gene and the PCAP (predisposing for cancer of the prostate) gene are on chromosome 1, while the human prostate cancer gene is on the X chromosome.

Genetic studies suggest that a strong familial predisposition may be responsible for as many as 5-10% of prostate cancer cases. Men with a family history of prostate cancer have a higher risk of developing prostate cancer and are also likely to present 6-7 years earlier. Several reports have suggested a shared familial risk (inherited or environmental) for prostate and breast cancer. BRCA-2 mutations increase the risk for prostate cancer that is more aggressive and develops at a younger age. [6]

A study by Ewing et al found that germline mutations in HOXB13 may be a risk factor for prostate cancer. HOXB13 is a homeobox transcription factor gene that is important in prostate development. The G84E variant of this gene, while rare, is significantly more common in men with early onset, familial prostate cancer than in those with late-onset, nonfamilial prostate cancer. [8]

An examination of cancer histories of 198 Lynch syndrome families, including probands and their first- through fourth-degree relatives, found that men with Lynch syndrome have a two-fold increased risk of prostate cancer compared to the general population. Of the 4127 men involved in the study, 97 had prostate cancer. Median age at diagnosis was 65, with 11.5% diagnosed before age 50. The cumulative risk of prostate cancer for men with Lynch syndrome was 6.3% at age 60 and 30% at age 80, vs a population risk of 2.6% and 17.8%, respectively. [9, 10]

Diet

Diet may play a role in the development of prostate cancer. Epidemiologic studies have suggested a variety of dietary factors that may be associated with the disease, particularly fat intake and obesity. See Prostate Cancer and Nutrition for a complete discussion of this topic.

Hormones

Hormonal causes of prostate cancer have also been postulated. Androgen ablation causes a regression of prostate cancer. In addition, as indirect evidence of hormonal causes, eunuchs do not develop adenocarcinoma of the prostate.

Hsing and Comstock performed a large study comparing patients with prostate cancer with controls and found no significant difference in levels of testosterone, dihydrotestosterone, prolactin, follicle-stimulating hormone, or estrone. However, elevated levels of luteinizing hormone and of testosterone:dihydrotestosterone ratios were associated with mildly increased risk. [11]

5-alpha reductase

The Prostate Cancer Prevention Trial studied the prevalence of prostate cancer in a control group and in a group given a 5-alpha-reductase inhibitor (finasteride). [12] While the 5-alpha reductase inhibitor appeared to decrease the prevalence of tumors, some of those that did arise appeared histologically more aggressive. Only long-term follow-up of these patients will determine whether this more aggressive histology accurately reflects the underlying biology of these tumors or whether it is an artifact of the treatment.

A similar study was performed with dutasteride, a molecule that blocks not only D1 but also D2 receptors in the prostate. The investigators found a 22.8% relative risk reduction in the development of prostate cancer, but the study did not fully refute the concern that more aggressive cancers could arise in treated patients.

Possibly for this reason, when the concept of 5-alpha reductase for chemoprevention of prostate cancer was brought before the US Food and Drug Administration (FDA) in 2010, the FDA did not approve the drugs for this indication. [13, 14] Indeed, on June 9, 2011 the FDA announced revisions to the prescribing information for 5-alpha reductase inhibitors to include a warning regarding an increased incidence of high-grade prostate cancer in men taking dutasteride or finasteride compared with placebo. [15]

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Epidemiology

Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates being in North America, Australia, and northern and central Europe and the lowest rates being in southeastern and south-central Asia and northern Africa. [6]

Occurrence in the United States

In the United States, prostate cancer is the most common noncutaneous cancer in men. An estimated one in six white men and one in five African American men will be diagnosed with prostate cancer in their lifetime, with the likelihood increasing with age. The American Cancer Society estimates that 161,360 new cases of prostate cancer will be diagnosed in 2017. [6] Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years.

Between 1989 and 1992, incidence rates of prostate cancer increased dramatically in the United States, probably because of earlier diagnoses in asymptomatic men were being made as a result of the increased use of serum PSA testing. In addition, the incidence of organ-confined disease at diagnosis has increased because PSA testing and standard digital rectal examination are performed. Since 1992, incidence rates have declined markedly, decreasing from almost 250 per 100,000 population in 1992 to less than 150 per 100,000 population in 2011. [6]

A review of almost 800,000 cases of prostate cancer diagnosed from 2004–2013 found that although the incidence of low-risk prostate cancer decreased from 2007-2013 to 37% less than that of 2004, the annual incidence of metastatic prostate cancer during those years increased to 72% more than that of 2004. The increase in metastatic prostate cancer was greatest (92%) in men aged 55–69 years. [16]

Racial demographics

Prevalence rates of prostate cancer remain significantly higher in African-American men than in white men, while the prevalence in Hispanic men is similar to that of white men. The prevalence in men of Asian origin is lower than in whites. Although mortality rates are continuing to decline among white and African-American men, mortality rates in African-American men remain more than twice as high as in any other racial group. [6]

Hispanic men and African-American men present with more advanced disease. [17] Studies have found that young African-American men have testosterone levels that are 15% higher than in young white men. Furthermore, evidence indicates that 5-alpha reductase may be more active in African Americans than in whites, implying that hormonal differences may play a role. However, the independent contribution of race is difficult to isolate from the effects of health-care access, income, education, and insurance status.

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Prognosis

The most important and established indicators of prognosis for prostate carcinoma include the Gleason grade, the extent of tumor volume, and the presence of capsular penetration or margin positivity at the time of prostatectomy. High-grade prostate cancer, particularly the percentage of Gleason grades 4 and 5 that are present, is associated with adverse pathologic findings and disease progression. Conversely, low-grade prostate tumors are infrequently dangerous.

In a review of 11,521 patients treated with radical prostatectomy at 4 academic centers from 1987 to 2005, Eggener et al reported an overall 15-year prostate cancer–specific mortality rate of 7%. High-grade cancer and seminal vesicle invasion were the prime determinants of prostate cancer–specific mortality. [18]

Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, from 20% in the 1970s to 3.4% in the 1990s, the risk of extra-prostatic disease in patients with clinically localized disease remains high at approximately 30%. Depending on the PSA value, pathologic stage, and histologic grade of the tumor, approximately 30% of patients with clinically localized prostate cancer are estimated to progress despite initial treatment with intent to cure.

The Cancer of the Prostate Risk Assessment (CAPRA) score for predicting prognosis is calculated on the basis of the following:

  • PSA level
  • Gleason score
  • Percentage of biopsy cores positive for cancer
  • Clinical tumor stage
  • Age at diagnosis

In a study of 10,627 men with clinically localized prostate cancer who underwent primary radical prostatectomy, radiation therapy, androgen deprivation monotherapy, or watchful waiting/active surveillance, and had at least 6 months of follow-up after treatment, Cooperberg et al found that the CAPRA score was accurate for predicting metastases, cancer-specific mortality, and all-cause mortality. [19]

In a retrospective study of patients who underwent radical retropubic prostatectomies, researchers found an association between an opioid-sparing approach to anesthesia and reductions in prostate cancer progression and overall mortality. The investigators reviewed 1642 procedures performed with general anesthesia and 1642 prostatectomies performed with an opioid-sparing approach (general anesthesia supplemented with a neuraxial block), in patients diagnosed with prostate cancer between 1991 and 2005. Median follow-up in the study was 9 years. [20, 21] Results indicated that the risk of systemic progression of prostate cancer was almost 3 times greater and the mortality risk was 30% higher in the general anesthesia patients than in patients anesthetized with an opioid-sparing approach. [20, 21]

In a multivariate analysis, biochemical recurrence and disease-specific mortality were much higher in men who were smokers at the time of diagnosis versus those who had never smoked. A higher number of pack-years was associated with significantly increased risk for prostate cancer mortality but not for biochemical recurrence. Men who had quit smoking 10 years prior to diagnosis—or who had quit more recently but smoked for <20 pack-years—had prostate cancer–mortality risks much like those of men who had never smoked. [22]

In a retrospective study at Johns Hopkins Medical Center in Baltimore, a greater connection between cigarette smoking and risk of prostate cancer recurrence was identified in men who had been treated with radical prostatectomy. [23] Without prospective studies, however, these relationships remain hypothetical.

In an analysis of two large cohort studies of health professionals, researchers found a significantly increased risk for melanoma among men with prostate cancer. In 42,372 participants in the Health Professionals’ Follow-Up Study, a history of prostate cancer was independently associated with an increased risk for melanoma (hazard ratio, 1.83). This association was confirmed in an analysis of 18,603 participants in the Physicians’ Health Study (hazard ratio, 2.17). [24, 25]

Molecular prognostic markers

Several molecular markers have been shown to aid in determining the prognosis of patients undergoing treatment for localized and metastatic prostate cancers. Genetic changes associated with poor survival in prostate cancer include the following [26] :

  • Loss of one or both copies of the tumor suppressor gene PTEN
  • TMPRSS2–ERG chromosome fusion (fusion of an androgen-responsive promoter with the ERG transcription factor)
  • P53 mutations
  • Overexpression of MYC

Assessments of molecular alterations of gene products of RB, BCL2, cathepsin-D, and CDH1, among many others, have also been reported. Decreased expression of the cell cycle inhibitor p27 in prostate cancer cells has been associated with increased risk of prostate cancer recurrence. [27]

Prospective trials are needed to assess these markers more thoroughly before their implementation in clinical management is recommended. Currently, none of them are measured in routine practice.

Prognostic nomograms

The Partin tables are the best nomogram for predicting prostate cancer spread prior to therapy. The tables were updated by experts at Johns Hopkins in January 2013. Updates to the tool were based on a study of 5629 men who underwent radical prostatectomy and staging lymphadenectomy between 2006 and 2011. The updated tables show that certain categories of men who were previously not thought to have a good prognosis (eg, those with a Gleason score of 8) actually can be cured with surgery. [28, 29]

In addition, a series of nomograms has been developed from the Memorial Sloan-Kettering Cancer Center that is used to predict disease progression and survival after a variety of treatments.

Morbidity and mortality

Current prostate cancer treatments, including radical prostatectomy and radiation therapy, result in permanent side effects in many men. The most common ones are erectile dysfunction and urinary incontinence. [30]

A comparison of functional outcomes in African-American versus non–African-American patients found no statistically significant difference in urinary and sexual outcomes 6 months after robotic-assisted radical prostatectomy. At 12 months, however, African-American patients had lower rates of adequate erectile function (60% vs 76.4%) and urinary continence (55.7% vs 69.8% ) compared with non–African Americans. [31]

Margel et al found that radiation therapy for prostate cancer may be associated with slightly increased risk of secondary malignancy, such as rectal cancer and bladder cancer. [32] In this study, rectal cancer occurring after radiation therapy was diagnosed at a more advanced stage and resulted in lower disease-specific survival.

Prostate cancer is the second most common cause of cancer death in males, after lung cancer. The American Cancer Society estimates that 26,120 men will die from the disease in 2016. [6]  However, in contrast with lung cancer, which accounts for 14% of new cases but 27% of cancer deaths in men, prostate cancer accounts for 21% of new cases but only 8% of deaths. [6]

Death rates from prostate cancer rose steadily from 1975 to 1991, remained level from 1991 to 1994, and have decreased since then. [6] Although this decrease has been dismissed as an artifact of lead-time bias, earlier diagnosis of progressive disease and improvements in the treatment of advanced disease are the most likely driving force behind the mortality reduction.

In the United States from 2004 to 2010, 5-year relative survival rates were greater than 99% in men with local or regional prostate cancer at diagnosis. In men with distant disease, however, survival was only 28%. [6]

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Patient Education

With the advent of PSA screening, and in the absence of level I studies comparing the various options, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated. Such education allows patients to make informed decisions about screening and, in men diagnosed with prostate cancer, to select the most appropriate treatment. Up-to-date information is available through the National Cancer Institute and the American Cancer Society, as well as Prostate Videos.com.

For patient education information, see the Men's Health Center and the Cancer Center, as well as Prostate Cancer, Enlarged Prostate (Benign Prostatic Hyperplasia or BPH), and Cancer: What You Need to Know.

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