Prostate Cancer 

  • Author: Tracey L Krupski, MD, MPH; Chief Editor: Edward David Kim, MD, FACS   more...
 
Updated: Apr 23, 2012
 

Background

Prostate cancer is the most common noncutaneous cancer among males. Although prostate cancer can be a slow-growing cancer, thousands of men die of the disease each year; prostate cancer 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 important (see Etiology).

Currently, 47% 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 Clinical Presentation).

Screening for prostate cancer is a controversial topic, in large part because of the limited understanding of the natural history of the disease (see Workup). Education is important to help men make informed decisions regarding the screening and, in those diagnosed with prostate cancer, the various treatment options.

Standard treatments for clinically localized prostate cancer include radical prostatectomy, radiation therapy, cryotherapy, or active surveillance. The historic term of watchful waiting suggested waiting for symptoms to develop, not actively observing for progression. Management of locally advanced prostate cancer is often with external beam radiotherapy. For these tumors, radiation therapy along with androgen ablation is generally recommended, although radical prostatectomy may be appropriate as an alternative to radiation therapy in some cases (see Treatment and Management).

The biopsy grade, clinical stage, and PSA level provide prognostic information that helps stratify patients to particular treatments. Patient preference plays an important role in treatment decisions.

Androgen deprivation therapy is considered the primary approach in the treatment of symptomatic metastatic prostate cancer. However, androgen deprivation therapy has been found to be palliative, not curative, in metastatic disease.

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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 diagManagement 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 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 (95%) prostate cancers 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. 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.

Squamous cell carcinomas constitute less than 1% of all prostate carcinomas. In many cases, prostate carcinomas with squamous differentiation arise after radiation or hormonal 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, 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 attributes metastasis to direct spread through the lymphatics and venous spaces into the lower lumbar spine. Advocates of the seed-and-soil theory 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 as slow as 2-4 years, but this tends to accelerate as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.

Natural history by stage is as follows:

  • T1a - Progression over 10 years (uncommon)
  • T1b - Tumor-related death rate of 10% in 10 years
  • T2 - Ten-year metastasis-free survival rate of 81% with grade 1, 58% with grade 2, and 26% with grade 3
  • T3 - Lymph node metastasis at presentation in 50% and approximately 25% rate of 10-year disease-free survival

The natural history of clinically localized disease varies, with lower-grade tumors having a more indolent course, while some high-grade lesions progress to metastatic disease with relative rapidity. Given the typically slow progression of localized disease, several studies have examined the strategy of active surveillance in these cases.

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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 suggest the importance of environmental factors, notably diet.[1] Familial predisposition also occurs.

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.[2] 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 hereditary prostate cancer 1 (HPC1) gene and the predisposing for cancer of the prostate (PCAP) 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.[1]

A study by Ewing found that germline mutations in HOXB13 may be a genetic risk factor for prostate cancer.[3]

Diet

Diet plays a role in the development of prostate cancer. Epidemiological studies have identified a variety of dietary factors, particularly fat intake and obesity. See Prostate Cancer and Nutrition for a complete discussion of this topic.

Hormones

Hormonal causes 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.[4]

5-Alpha reductase

The Prostate Cancer Prevention Trial studied the prevalence of prostate cancer between a control group and a group given a 5-alpha-reductase inhibitor (finasteride).[5] While the 5-alpha reductase inhibitor appeared to decrease the prevalence of tumors, 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. These authors also found a 22.8% relative risk reduction in the development of prostate cancer and did not fully refute the concern about more aggressive cancers. 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, they did not approve the drugs for this indication.[6, 7]

On June 9, 2011 the US Food and Drug Administration announced revisions to the prescribing information for 5-alpha reductase inhibitors (5-ARIs) to include a warning regarding an increased incidence of high-grade prostate cancer in men taking dutasteride or finasteride compared with placebo.

A 2012 study investigated the safety and efficacy of dutasteride on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance. Participants were randomized to receive once-daily dutasteride or matching placebo. At 3-year follow-up, 38% of men in the dutasteride group and 48% of controls had prostate cancer progression. Equal percentages across both groups (5%) had cardiovascular adverse events. However, there were no prostate cancer-related deaths or instances of metastatic disease. Results suggest dutasteride could be a beneficial supplement to active surveillance.[8]

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Epidemiology

Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates in North America, Australia, and northern and central Europe and the lowest rates in southeastern and south central Asia and northern Africa.[1]

In the United States, prostate cancer is the most common noncutaneous cancer among males. An estimated 1 in 6 whites and 1 in 5 African Americans will develop prostate cancer in their lifetime, with the likelihood increasing with age. The American Cancer Society estimated that 217,730 new cases of prostate cancer would be diagnosed in 2010.[1] 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 US, probably because of earlier diagnoses in asymptomatic men as a result of the increased use of serum PSA testing. In fact, the incidence of organ-confined disease at diagnosis has increased because both PSA testing and standard digital rectal examination are performed.

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, such as diet, may play a significant promoting role in the development of a clinical cancer secondary to a latent precursor.

In a multivariate analysis, the risks for biochemical recurrence and disease-specific mortality were much higher for men who were smokers at the time of diagnosis versus those who had never smoked. Being exposed to a greater 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.[9] 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.[10]

Because of its genetic linkage, prostate cancer is more common in males with a strong family history of prostate cancer. Likewise, people who smoke, African American males, and patients who consume a diet high in animal fat or high in chromium are at an increased risk.

Prostate cancer mortality

Prostate cancer is the second most common cause of cancer death in males, after lung cancer. The American Cancer Society estimated that 32,050 men would die from the disease in 2010.[1]

Death rates from prostate cancer rose steadily from 1975 to 1991, remained level from 1991 to 1994, and has decreased since then.[1] This decrease has been attributed to early diagnosis with routine screening and successful intervention; on the other hand, it has also been dismissed as an artifact of lead-time bias.

Continued patient follow-up from completed clinical trials (eg, the Prostate Intervention Versus Observation Trial [PIVOT]) should clarify this point of contention. Regardless, it is important to understand that more men die with prostate cancer than of prostate cancer. Postmortem study findings suggest that up to 80% of men older than 80 years have occult prostate cancer.

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 twice as high as in white men, based on 2008 American Cancer Society projections.

Hispanic men and African American men present with more advanced disease.[11] 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 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 percent presence of Gleason grades 4 and 5, is associated with adverse pathologic findings and disease progression. Conversely, low-grade prostate tumors can also be biologically aggressive.

Prognosis by treatment modality

The ranges of the disease-free 10-year survival rates for early localized disease listed below are wide because the outcomes of these treatments vary as a function of tumor aggressiveness (ie, as indicated by Gleason score and PSA level). In addition, series from various institutions show significant differences.

  • Radical prostatectomy (80-95%)
  • Brachytherapy and external radiation (80-95%)
  • Watchful waiting (50-73%)

In a study of men with early prostate cancer (stage T1b, T1c, or T2), Holmberg et al found that over a median of about 6 years followup, death from prostate cancer was lower in patients treated with surgery compared with watchful waiting (4.6% vs 8.9%).[12] In patients with advanced localized disease, the disease-specific 10-year survival rate for advanced localized disease in patients treated with brachytherapy and external radiation is 40-62%.

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 extraprostatic disease in patients with clinically localized disease remains high, at 30-60%. 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.

Cooperberg et al built and validated a model for risk prediction specifically intended for use in patients receiving primary androgen deprivation therapy for prostate cancer, the Japan Cancer of the Prostate Risk Assessment (J-CAPRA). J-CAPRA is scored from 0-12 based on Gleason score, PSA level, and clinical stage.

J-CAPRA predicted progression-free survival with a c-index of 0.71 among 13,740 men in a United States registry and predicted cancer-specific survival with a c-index of 0.84 among 19,265 men in a Japanese registry.[13]

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. Assessments of the molecular alterations or gene products of TP53, RB, BCL2, cathepsin-D, CDH1, and PTEN, among many others, have been reported. Prospective trials are needed to assess these markers more thoroughly before their implementation in clinical management is recommended.

Decreased nuclear expression of the cell cycle inhibitor p27 has been associated with poor outcome in prostate cancer according to previous studies. Ananthanarayanan et al developed and studied an automated method for subcellular scoring of p27 that does not require the segmenting of individual cells. This method of laser-based fluorescence microscopy showed a strong relationship, aside from tumor grade, stage, and prostate-specific antigen, between decreased p27 expression and increased risk of prostate cancer recurrence, regardless of subcellular location. This relationship was not seen via manual scoring.[14]

Prognostic nomograms

The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis. In addition, a series of nomograms has been issued from the Memorial Sloan-Kettering Cancer Center; these nomograms are used to predict disease progression and survival after a variety of treatments.

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Patient Education

With the advent of PSA screening, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated. This will allow patients to make informed decisions about screening and, in those diagnosed with prostate cancer, to select the most appropriate treatment.

For patient education information, see the Prostate Cancer site, as well as Prostate Health Center, Enlarged Prostate, Men's Health Center, Cancer and Tumors Center, and Cancer: What You Need to Know.

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Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

Tracey L Krupski, MD, MPH  Assistant Professor, Department of Urology, University of Virginia School of Medicine

Tracey L Krupski, MD, MPH is a member of the following medical societies: American Medical Association, American Society of Clinical Oncology, American Urological Association, and Society of Women in Urology

Disclosure: Nothing to disclose.

Coauthor(s)

Dan Theodorescu, MD, PhD  Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center

Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology

Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership

Chief Editor

Edward David Kim, MD, FACS  Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, Sexual Medicine Society of North America, and Tennessee Medical Association

Disclosure: Lilly Consulting fee Advisor; Astellas Consulting fee Speaking and teaching; Watson Consulting fee Speaking and teaching; Allergan Consulting fee Speaking and teaching

Additional Contributors

Isamettin Andrew Aral, MD, MSc Attending Physician, Nassau Radiologic Group (Long Island Radiation Therapy); Clinical Assistant Professor of Radiation Oncology, State University of New York Downstate College of Medicine

Isamettin Andrew Aral, MD, MSc, is a member of the following medical societies: American College of Radiology, American Medical Association, and American Society for Therapeutic Radiology and Oncology

Disclosure: Nothing to disclose.

Hassan Aziz, MD Clinical Professor, Department of Radiation Oncology, Downstate Medical Center and Long Island College Hospital, State University of New York at Downstate

Hassan Aziz, MD is a member of the following medical societies: American College of Radiology and American Society for Therapeutic Radiology and Oncology

Disclosure: Nothing to disclose.

Michael Giasullo, MD Clinical Assistant Professor, Department of Urology, State University of New York Downstate Medical Center; Chief, Department of Surgery, Division of Urology, Lutheran Medical Center; Consulting Staff, Bay Ridge Urology Associates; Assistant Attending Physician, Department of Surgery, Urology Section, Methodist Hospital

Michael Giasullo, MD is a member of the following medical societies: American Medical Association and American Urological Association

Disclosure: Nothing to disclose.

Leonard Gabriel Gomella, MD, FACS The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Leonard Gabriel Gomella, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Laser Medicine and Surgery, American Urological Association, Sigma Xi, Society for Basic Urologic Research, Society of University Urologists, and Society of Urologic Oncology

Disclosure: GSK Consulting fee Consulting; Astra Zeneca Honoraria Speaking and teaching; Watson Pharmaceuticals Consulting fee Consulting

Fazal Hussain, MD, MBBS Director, Clinical Research, King Faisal Cancer Centre

Fazal Hussain, MD, MBBS is a member of the following medical societies: American College of Radiology

Disclosure: Nothing to disclose.

Nicholas Karanikolas, MD Associate Professor, Department of Urology, SUNY Downstate College of Medicine; Director, Urologic Oncology, Staten Island University Hospital; Attending Physician, Department of Urology, Brooklyn Veterans Administration Hospital

Nicholas Karanikolas, MD is a member of the following medical societies: American Urological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Management of localized prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.
Management of localized prostate cancer. This photo illustrates the histologic scoring system (Gleason score) derived from the two most common patterns seen on the biopsy specimen.
Histologic scoring system showing the 2 most common patterns seen on the biopsy specimen, termed the Gleason score.
 
 
 
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