Etiology

The exact etiology of prostate cancer is unknown. However, several etiologic factors have been suggested.

High-fat diet

First proposed as a potential contributing factor for prostate cancer after a study of Asian immigrants living in the US found that they had a higher incidence of prostate cancer than men living in Japan or China.[12][13] Several studies have reported that high-fat diets may increase the risk of prostate cancer.[14][15][16][17] However, the evidence is inconsistent and the exact mechanisms are unclear.[15][16][17][18][19]

Genetic factors

Risk of prostate cancer is increased in men with a positive family history of prostate cancer.[20] One meta-analysis reported a pooled relative risk (RR) of 2.48 in men with one first-degree relative (brother or father) with prostate cancer compared with no first-degree family history.[20] Risk was higher if the first-degree relative was a brother (RR 3.14) rather than a father (RR 2.35). A RR of 4.39 was reported in men with two or more first-degree relatives with a history of prostate cancer. 

The genetic basis for this hereditary cause is unclear, but prostate-cancer specific germline mutations (e.g., HOXB13) have been implicated.[21] Germline mutations that increase the risk of prostate and other cancers have been identified:[22][23][24]​​​​

  • Homologous recombination DNA repair gene mutations (e.g., BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51D)

  • DNA mismatch repair gene mutations (e.g., MLH1, MSH2, PMS2, MSH6)

Ethnicity

In the US, non-Hispanic black men have the highest incidence of prostate cancer of any ethnic group (188.7 per 100,000).[1] Analysis of incidence data suggests that black men have a higher risk of developing preclinical prostate cancer and a higher risk of progression to metastatic disease. The reason for this is unknown.[25][26]​

Hormonal influence

There is conflicting evidence regarding the impact of hormonal influence on the direct cause of prostate cancer.

Pathophysiology

High-grade prostatic intraepithelial neoplasia (PIN) is the histologic entity widely considered to be the most likely precursor of invasive prostate cancer.[27] PIN is characterized by cellular proliferation within preexisting ducts and glands with cytologic changes that mimic neoplasm. PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer. In one study, 100 patients with high-grade PIN were compared with 112 patients without PIN.[28] Prostate cancer was identified in 35% of subsequent biopsies from the PIN group and 13% in the group without PIN. High-grade PIN, patient age, and prostate-specific antigen levels were highly significant predictors of prostate cancer, with PIN having a risk ratio of 14.93.

Prostate cancer tends to spread along the capsular surface of the gland and may invade the seminal vesicles, periprostatic tissue, and eventually the bladder neck. Subsequent spread can be to the perineural spaces, lymphatics, and blood vessels, which results in hematogenous metastases. In an autopsy study of 1589 men with prostate cancer performed from 1967 to 1995, hematogenous metastases were present in 35% of patients, with most frequent involvement being bone (90%), then lung (46%), liver (25%), pleura (21%), and adrenals (13%).[29]

Classification

American Joint Committee on Cancer (AJCC) TNM staging system (8th edition)[2]

The AJCC staging system describes the extent of disease based on the following anatomic factors: size and extent of the primary tumor (T) (assessed clinically [cT] and pathologically [pT]); regional lymph node involvement (N) (assessed clinically [cN] and pathologically [pN]); and presence or absence of distant metastases (M). Nonanatomic prognostic factors (e.g., serum prostate-specific antigen [PSA] level, and histology/biopsy of the primary tumor) are used to supplement staging.

National Comprehensive Cancer Network (NCCN) risk groups for clinically localized prostate cancer[3]​

  • Very low risk:

    • Has all of the following:

      • cT1c

      • Grade Group 1

      • PSA <10 nanograms/mL

      • <3 biopsy prostate biopsy fragments/cores positive, and ≤50% cancer in each fragment/core

      • PSA density <0.15 nanograms/mL/g

  • Low risk:

    • Has all of the following but does not qualify for very low risk:

      • cT1-cT2a

      • Grade Group 1

      • PSA <10 nanograms/mL

  • Favorable intermediate risk:

    • Has no high-risk or very high-risk features, AND

    • All of the following:

      • One of the following intermediate risk factors: cT2b-c; Grade Group 2; or PSA 10-20 nanograms/mL

      • Grade Group 1 (if not grade group 2)

      • Percentage of positive biopsy cores <50%

  • Unfavorable intermediate risk:

    • Has no high-risk or very high-risk features, AND

    • One or more of the following:

      • Two or three of the following intermediate risk factors: cT2b-c; Grade Group 2 or 3; and/or PSA 10-20 nanograms/mL

      • Grade Group 3 alone

      • Percentage of positive biopsy cores ≥50%

  • High risk:

    • Has no very high-risk features, AND

    • One of the following high-risk features:

      • cT3a

      • Grade Group 4 or 5

      • PSA >20 nanograms/mL

  • Very high risk:

    • Has at least one of the following:

      • cT3b-cT4

      • Primary Gleason pattern 5

      • Two or three high-risk features

      • >4 cores with Grade Group 4 or 5

Cancer of the Prostate Risk Assessment (CAPRA) score[4]

Used to predict the risk of metastases, prostate cancer-specific mortality, and overall mortality in prostate cancer patients.

The score is calculated by assigning points to five variables: age at diagnosis, PSA level at diagnosis, Gleason score (Grade Group), clinical tumor stage, and percentage of biopsy cores positive. UCSF: CAPRA score Opens in new window The CAPRA score (ranging from 0-10) is the sum of points from each variable. 

Patients are classified into one of the following risk groups based on their score:

  • Low-risk: CAPRA score of 0-2

  • Intermediate-risk: CAPRA score of 3-5

  • High-risk: CAPRA score of 6-10

Cambridge Prognostic Group (CPG) 5-tier risk stratification model for localized or locally advanced prostate cancer[5][6][7]

Patients with localized or locally advanced prostate cancer are classified into one of the following five risk groups based on Gleason score (Grade Group), PSA level at diagnosis, and/or tumor stage:

  • CPG 1:

    • All of the following:

      • Gleason score 6 (Grade Group 1)

      • PSA <10 nanograms/mL

      • Stage T1-T2

  • CPG 2:

    • Gleason score 3 + 4 = 7 (Grade Group 2) or PSA 10-20 nanograms/mL

      AND

    • Stage T1-T2

  • CPG 3:

    • All of the following:

      • Gleason score 3 + 4 = 7 (Grade Group 2)

      • PSA 10-20 nanograms/mL

      • Stage T1-T2

      OR

    • All of the following:

      • Gleason score 4 + 3 = 7 (Grade Group 3)

      • Stage T1-T2

  • CPG 4:

    • One of the following:

      • Gleason score 8 (Grade Group 4)

      • PSA >20 nanograms/mL

      • Stage T3

  • CPG 5:

    • More than one of the following:

      • Gleason score 8 (Grade Group 4)

      • PSA >20 nanograms/mL

      • Stage T3

      OR

    • Gleason score 9 or 10 (Grade Group 5)

      OR

    • Stage T4

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