Prostate Cancer

Updated: Sep 23, 2020
  • Author: Chad R Tracy, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Overview

Practice Essentials

Prostate cancer represents the second most common cancer in men worldwide and the fifth most common cause of cancer death in men; in the United States, it is the most common cancer in men and the second most common cause of cancer deaths in men. [1, 2] Acinar adenocarcinoma of the prostate comprises 90-95% of prostate cancers diagnosed. [3] Ductal carcinoma and neuroendocrine carcinoma account for the majority of additional cases. The 2016 World Health Organization classification provides a comprehensive listing of prostate tumors, including acinar adenocarcinoma subtypes. [4] In this article, the term prostate cancer refers to prostatic acinar adenocarcinoma.

The image below depicts the anatomic associations of the male urinary tract. The prostate lies between the bladder and the urogenital diaphragm. Owing to its anatomic location, the prostate may be palpable transrectally and accessed for biopsy via either the rectum or the perineum. For a more detailed description of prostate biopsy, see Workup/Prostate Biopsy

Prostate cancer. This diagram depicts the relevant Prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.

For additional information please see Prostate Cancer: Diagnosis and Staging, a Critical Images slideshow, to help determine the best diagnostic approach for this potentially deadly disease and/or Advanced Prostate Cancer: Signs of Metastatic Disease, a Critical Images slideshow, for help identifying the signs of metastatic disease.

Signs and symptoms

Most patients presenting with prostate cancer do so with screen-detected cancer and are asymptomatic. Local symptoms associated with prostate cancer can include:

  • Lower urinary tract symptoms (LUTS)
  • Hematuria
  • Hematospermia
  • Erectile dysfunction
  • Urinary retention

However, those symptoms are generally not caused by prostate cancer. Physical examination alone cannot reliably differentiate benign prostatic disease from cancer. [5]

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
  • Neuropathy

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 [6]  to about 25% with PSA levels of 4-10 ng/mL and over 50% for levels over 10 ng/mL [6]

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

Multiple institutions and collaborative groups have addressed prostate cancer screening. The United States Preventive Services Task Force (USPSTF) recomended against prostate cancer screening in 2011-2012, but in 2018 reversed the recommendation to include screening after an informed discussion. 

The evidence for and against screening, a summary of screening guidelines, and the observed impact of the USPSTF guidelines on prostate cancer incidence and mortality are presented in full detail in Workup/Prostate Cancer Screening

Management

Localized prostate cancer

Standard treatments for clinically localized prostate cancer include the following:

  • Watchful waiting 
  • Active surveillance
  • Radical prostatectomy
  • Radiation therapy

Emerging treatments with limited long-term data include targeted therapy and whole-gland ablation. 

Non-localized or recurrent prostate cancer

Prostate cancer may recur in up to a third of men after definitive local therapy. This disease state is now subdivided into castrate-sensitive or castrate-resistant locally recurrent prostate cancer and castrate-sensitive or castrate-resistant metastatic prostate cancer. These disease states are rarely curable, but recent advances in the understanding of salvage radiation therapy, chemohormonal therapy, androgen blockade, and poly(ADP-ribose) polymerase (PARP) inhibition has greatly prolonged survival for these men. For full discussion of this rapidly developing field, see Metastatic and Advanced Prostate Cancer.

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Background

Prostate cancer is the most common noncutaneous cancer in men in the United States. Although prostate cancer can be slow growing, thousands of men die of the disease each year. It is the second most common cause of cancer death in US 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.)

If detected, prostate cancer is assigned a grade and stage followed by a risk group determination for consideration of therapy. Prostate cancer grading has traditionally been performed according to the Gleason Grading system. In this two-number system, the first number is assigned to the predominant focus of tumor and the second, to the second more predominant pattern (see the image below); each is graded on a scale of 1-5 and the sum of the two is the overall grade. [7] Generally, the cut-off for prostate cancer starts with Gleason grade 3+3. However, the International Society of Urological Pathology (ISUP) has modified the Gleason system to a grade group system such that grade group 1 now encompasses Gleason 3+3 disease (see the Table below) 

Prostate cancer. 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.

Table 1. Comparison of Gleason grade and modern Grade Groups. (Open Table in a new window)

Gleason Grade Grade Groups
3+3 1
3+4 2
4+3 3
4+4, 3+5, 5+3 4
4+5, 5+4, 5+5 5

See also the following Medscape articles:

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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.)

Prostate cancer. This diagram depicts the relevant 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. Venous drainage of the prostate occurs via the dorsal vein and Santorini's plexus, the latter of which might be responsible for hematogenous spread to the axial skeleton. 

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Pathophysiology

Prostate cancer develops when the rates of cell division exceed those of cell death, 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 (90%) are adenocarcinomas.

Rarely, cancers may arise from the urothelial lining of the prostatic urethra. These are not prostatic adenocarcinomas but are treated as urothelial cancers. 

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. Cancer spreads to bone early, often without significant lymphadenopathy. 

Natural history

Undiagnosed prostate cancer that does not affect survival has been frequently described. Incidental, unsuspected prostate cancers have been noted in 25-40% of prostate specimens when the bladder and prostate are removed for male bladder cancers. [8] Latent prostate cancer has been described in numerous autopsy studies across several countries. Pooled analysis of several studies suggest that the prevalence of incidental prostate cancer at autopsy doubles for approximately every 14 years of life, with most of these cancer being of low Gleason grade. [9]

Taken together, the prevalence of indolent prostate cancer combined with the lethality of some cases would suggest a spectrum of prostate cancer ranging from cancer that men die with and that which men die from. Indeed, a pooled analysis of several natural history evaluations would suggest that low-grade (Gleason 5-6) disease requires 10-15 years of lead time to develop into aggressive disease while higher-grade disease is associated with poor disease-specific mortality at 10 years if left untreated. [10] It should be noted that Gleason 5 disease is no longer considered cancer.

With the advent of prostate cancer screening in the 1990’s, several epidemiologic evaluations have demonstrated a significant stage migration and improvements in prostate cancer mortality and thus the natural history, though with the caveat of overtreatment. [11, 12, 13] This is discussed in greater detail in Workup/Prostate Cancer Screening

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Epidemiology and Etiology

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. [1, 14]

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 Black men will be diagnosed with prostate cancer in their lifetime, with the likelihood increasing with age. The American Cancer Society estimates that 191,930 new cases of prostate cancer will be diagnosed in 2020.Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years. [2]

Between 1989 and 1992, incidence rates of prostate cancer increased dramatically in the United States, probably because of earlier diagnoses in asymptomatic men 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 over 230 per 100,000 population to less than 110 per 100,000 population in 2013-2017. [2, 15]

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]

Age-related demographics

Prostate cancer incidence increases as men age; as many as 60% of men over 65 years of age may be diagnosed with prostate cancer. [14] Prostate cancer is most often diagnosed in men aged 65-74 years; median age at diagnosis is 66 years. [15]

However, men as young as 17 years are experiencing an increasing incidence of prostate cancer in much of the world, including the United States, according to data from the Surveillance, Epidemiology, and End Results (SEER) program and the Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease (GBD) database. These younger patients frequently present with more advanced cancer and have worse survival than middle-aged and older men. Worldwide, the incidence of prostate cancer has increased in men ages 15 to 40 years at a steady rate averaging 2% per year since 1990. In the United States, this age group was more than 6 times more likely than older men to have distant disease at diagnosis. [17]

Racial demographics

Significant racial disparity in the incidence and mortality exists, with prostate cancer–specific mortality over 2-fold higher in Blacks than in Whites. [18] Worldwide, the incidence is highest in Blacks and Caribbean men of African descent, followed by Whites, Hispanics, and finally Asian men living in their native countries. Prostate cancer incidence is highest in countries with the highest socioeconomic index. [19]

Risk factors

Well-established risk factors for prostate include ethnicity, age, and country of residence. Additional risk factors include family history and genetic predisposition. For men with a family history (1 or more first-degree relatives) of breast cancer, the risk of prostate cancer diagnosis increases by 21%, and lethality increases by 34% compared with those without such history. Similarly, a family history of prostate cancer increases risk by 68% and lethality of disease by 72%, with a general trend favoring increases in risk according to earlier cancer onset in families. [20] These associations have led to the identification of several germline mutations associated with hereditary prostate cancer, including HOXB13,BRCA1, BRCA2, DNA mismatch repair genes, ATM, CHEK2, PALB2, NBN, and RAD51D. [21]

Discovery of these mutations has led to recommendations for the consideration of genetic testing for men with family histories that strongly suggest the presence of these mutations and men with metastatic castrate-resistant prostate cancer. [21, 22] In men referred for genetic testing, about 20% will have a known genetic variation while only 63% will have a significant family history that would guide genetic testing decision making. [23] BRCA1/2 and ATM mutations have been found in significantly higher rates for men with lethal prostate cancer. [24] Overall, genetic testing remains a novel and developing area of prostate cancer research, but may ultimately inform screening, risk stratification, treatment aggressiveness, and (where currently applied) targeted systemic therapy for advanced disease. [25]

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 2-fold higher risk of prostate cancer compared with 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, versus a population-wide risk of 2.6% and 17.8%, respectively. [26]

Several additional risk factors are associated with either prostate cancer incidence but with lower levels of evidence, or conflicting evidence. Both increased body mass index (BMI) and additional components of the metabolic syndrome (eg, hyperinsulinemia, waist circumference) have been variably associated with both increased prostate cancer incidence and possibly increased recurrence after definitive therapy. [27, 28, 29, 30, 31]

Tobacco smoking, nutritional supplementation and/or deficiency, activity, and dietary components have also demonstrated variable association with prostate cancer incidence and/or mortality. [32] Supplementation with selenium and vitamin E were prospectively evaluated for the prevention of the prostate cancer in the SELECT trial, which demonstrated an increase in prostate cancer cases for those given vitamin E only and no effect of selenium supplementation. [33] The effect observed for vitamin E was not seen in other studies. [34] The significant heterogeneity surrounding these risk factors suggests that further, nuanced evaluation is required before they can be classified as risk factors for prostate cancer or prostate cancer severity.

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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. [35]

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% clinically localized prostate cancers 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. [36]

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. [37]

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. [38] 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). [39]

Molecular prognostic markers

Several prognostic tests have been shown to aid in determining the risk of harboring aggressive disease for patients with localized prostate cancers. This is an area of rapid change. Consensus regarding the applicability of different markers based on clinical scenarios remains elusive. Lamy and colleagues have published a detailed review of prognostic biomarkers used for management of localized prostate cancer. [40] For discussion of markers utilized in the post-surgery or metastatic setting, see Metastatic and Advanced Prostate Cancer.

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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 Prostate Cancer Health Center.

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