Contributors of Campbell-Walsh-Wein, 12th edition
Samuel L. Washington Iii, Andrew J. Stephenson, Robert Abouassaly, Eric A. Klein, Simpa S. Salami, Ganesh S. Palapattu, Alan W. Partin, Todd M. Morgan, Edouard J. Trabulsi, Ethan J. Halpern, Leonard G. Gomella, Onathan I. Epstein, Stacy Loeb, James A. Eastham, Samir S. Taneja, Marc A. Bjurlin, Laurence Klotz, Edward M. Schaeffer, Herbert Lepor, Li-Ming Su, Brandon J. Otto, Anthony J. Costello, Ryan Phillips, Sarah Hazell, Daniel Y. Song, Kae Jack Tay, Thomas J. Polascik, Maxwell V. Meng, Peter R. Carroll, Eugene K. Lee, J. Brantley Thrasher, Scott Eggener, Emmanuel S. Antonarakis, and Michael A. Carducci
Prostate cancer incidence and mortality
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Most common noncutaneous malignancy in US men: 191,930 cases per year.
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Second most common cause of cancer death in the United States: 33,330 per year.
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Globally second most common cancer, fifth leading cause of cancer deaths.
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Age-adjusted incidence rate 104.1 per 100,000 men per year.
Racial disparities in prostate cancer
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African American men have a 76% higher incidence and 60% higher cancer-specific mortality rate than white men.
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The incidence of prostate cancer in other ethnic groups is lower than that of whites and African Americans ( Table 22.1 )
Table 22.1
Prostate Cancer Incidence and Mortality by Race/Ethnicity, United States, 2009–2013
INCIDENCE a
MORTALITY RATE a
White
114.8
18.7
African American
198.4
42.8
Hispanic/Latino
104.9
16.5
Asian American and Pacific Islander
63.5
8.8
American Indian and Alaska Native
85.1
19.4
a Per 100,000, age adjusted to the 2000 US standard population.
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Differences in treatment patterns explain nearly half (48%) of the cancer-specific survival disparity after adjustments for demographics, tumor characteristics, and socioeconomic factors.
Screening controversy, incidence, and mortality
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Screening is recommended by the American Urological Association (AUA) guidelines for men between 55 and 69 years of age who have at least a 10-year life expectancy and who wish to be screened.
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Shared decision making about whether to screen for prostate cancer is recommended uniformly.
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Prostate-specific antigen (PSA) and digital rectal exam (DRE) and used to screen for prostate cancer.
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PSA levels may be affected by age, gland size, infection/inflammation, medications such as 5-α reductase inhibitors, recent diagnostic procedures, and prostate-directed treatments.
Trials
The US Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial found no difference in prostate cancer mortality between the screening and control groups through 15 years of follow-up. Concerns surrounding high rates of contamination, with an estimated 90% of patients in the control arm having received at least one PSA before or during the trial, question whether the trial actually compared annual screening versus none or whether it has been more accurately described as a comparison of organized screening versus opportunistic screening.
The European Randomized Study of Screening for Prostate Cancer (ERSPC) compared randomized between PSA screening every 4 years or no screening and men in the screening arm had a 57% (95% confidence interval [CI], 51–62) increased incidence of prostate cancer compared with controls and a 21% (95% CI, 9–31) relative reduction in death from prostate cancer (4.3 vs. 5.4 cancer deaths per 10,000 person-years) after a median follow-up of 13 years.
Soon after publication of the PLCO and ERSPC, the US Preventive Services Task Force (USPSTF) in 2012 recommended against routine PSA but later in April 2017 partially reversed its course and submitted new draft recommendations, giving a grade of C to prostate cancer screening in men 55–69 years of age (offered for selected patients) but keeping the grade of D for men 70 years of age and older (discouraging its use) at least partially in response to modeling studies suggesting an estimated 46%–57% increase in metastatic cases at presentation, leading to as much as a 20% increase in prostate cancer deaths.
Risk factors and chemoprevention
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Familial – Relative risk increases according to the number of affected family members, their degree of relatedness, and the age at which they were affected ( Table 22.2 )
Table 22.2
Family History and Risk for Prostate Cancer
FAMILY HISTORY
RELATIVE RISK
95% CONFIDENCE INTERVAL
Father affected at any age
2.35
2.02–2.72
Brother(s) affected at any age
3.14
2.37–4.15
One affected first-degree relative diagnosed at any age
2.48
2.25–2.74
Affected first-degree relatives diagnosed <65 years
2.87
2.21–3.74
Affected first-degree relatives diagnosed ≥65 years
1.92
1.49–2.47
Second-degree relatives diagnosed at any age
2.52
0.99–6.46
Two or more affected first-degree relatives diagnosed at any age
4.39
2.61–7.39
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BRCA-Associated Cancers – Especially BRCA2, more likely to present with higher-grade, locally advanced, and metastatic disease and have poorer cancer-specific and metastasis-free survival after prostatectomy.
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Diet – No clear association between dietary fat intake and prostate cancer risk.
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Obesity – Associated with higher rates of biochemical failure after treatment and 15%–20% increase per 5 kg/m 2 increase in body mass index (BMI) in prostate-specific cancer mortality.
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The Selenium and Vitamin E Cancer Prevention (SELECT) Trial – A randomized, placebo-controlled, population-based primary chemoprevention trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer, demonstrated no effect on the risk for prostate cancer by either agent alone or in combination.
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Finasteride – The Prostate Cancer Prevention Trial (PCPT) showed a 25% reduction in the period prevalence of prostate cancer in men taking finasteride (18.4%) compared with placebo (24.4%) across all groups as defined by age, ethnicity, family history of prostate cancer, and PSA at study entry. However, a significant increase in the prevalence biopsy Gleason score 7 to 10 cancers was observed in men receiving finasteride (280 [37%]) compared with placebo (237 [22%]), particularly for biopsy Gleason score 8 to 10 cancers. In a secondary analysis of PCPT that adjusted for the effects of finasteride on the detection of prostate cancer, the adjusted prostate cancer rates were estimated to be 21.1% for the placebo group and 14.7% in the finasteride group, a 30% risk reduction for all cancers (hazard ratio [HR], 0.70; 95% CI, 0.64–0.76) and a nonstatistically significant 14% increase in high-grade cancer. Accounting for the increased probability of upgrading to pathologic Gleason 7 to 10 cancer at radical prostatectomy among men with biopsy Gleason 2 to 6 cancers in the placebo arm, the investigators estimated the rate of true high-grade cancer to be 6% in the finasteride arm and 8.2% in the placebo arm, representing a 27% relative risk reduction in the rate of true high-grade cancers in men treated with finasteride (HR, 0.73; 95% CI, 0.56–0.96).
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Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial – Randomized, placebo-controlled primary chemoprevention trial using dutasteride, which reduced the risk for prostate cancer over 4 years by 23%.
Prostate cancer biomarkers
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PSA Isoforms – Free PSA, pro PSA, human kallikrein, mRNA, and TMPRSS2:ERG fusion products have been measured and integrated into commercially available serum and urine tests for additional prognostication and decision making prior to biopsy ( Figs. 22.1 to 22.4 )
Fig. 22.4
PCA3 assay protocol. After “attentive” digital rectal exam, urine is collected. RT-PCR determines the mRNA levels for PCA3 and PSA. The ratio between PCA3/PSA determines the PCA3 score. Prostate cancer risk level suggests need for biopsy.
(From Groskopf J, Aubin SM, Deras IL, et al. APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem 2006;52:1089-1095.)
Fig. 22.3
CellSearch CTC: Circulating Tumor Cell (Veridex) cell enumeration system. CD45, CD stands for cluster of differentiation, which was originally called leukocyte common antigen. The anti-EpCAM ferrofluid captures the cells, and they are then validated with cytokeratin-positive and CD45-negative staining. CK, Cytokeratin; EpCAM, epithelial cell adhesion molecule.
Fig. 22.2
Prostate-specific antigen (PSA) synthesis in normal versus cancer tissue. ProPSA is secreted into the lumen, where the 7–amino acid leader sequence is cleaved by hK2 to yield active PSA. Some of the active PSA diffuses into the serum, where it is bound to proteases such as α 1 -antichymotrypsin (ACT). The luminal active PSA undergoes proteolysis, and the resulting inactive PSA (iPSA) may also enter the circulation to circulate in the unbound or free state. In prostate cancer, loss of the tissue architecture may permit a relative increase in bound PSA and proPSA in serum.
Fig. 22.1
Differential cleavage and activation of pro–prostate-specific antigen (PSA). ProPSA is released from the prostate epithelial cell with a 7–amino acid leader sequence. hK2 cleaves the amino acid leader to activate PSA. Active PSA undergoes proteolysis to yield inactive PSA (iPSA) and may also undergo internal degradation to form benign PSA (BPSA). Partial cleavage of the 7–amino acid leader sequence yields inactive forms of proPSA (i.e., [–2]pPSA or [–4]pPSA).
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PSA density (defined as the PSA value divided by the prostate gland size) predicts reclassification on surveillance biopsy.
Genomics
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Most Frequent Genomic Alterations – Fusions of androgen-regulated promoters with ERG and other ETS-family transcription factors, accounting for 53% of the cases.
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PTEN deletions in ERG fusion–positive cases and that tumors with SPOP mutations (accounting for ≈10% of cases).
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Most Common Fusion – TMPRSS2 or other promoters ( SLC45A3 and NDRG ) fused to ERG (ETS-related gene) in 50%–60% of patients.
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Data are mixed on whether the presence of TMPRSS2:ERG fusions affect prognosis.
Prostate biopsy
Organizations such as the AUA recommend shared decision making for men 55–69 years of age considering PSA-based screening, a target age group for whom benefits may outweigh harms. Most organizations are relying increasingly on risk stratification approaches and changes in PSA level over time. The National Comprehensive Cancer Network (NCCN) advocates the selective use of biomarkers, including PSA derivatives, tissue assays of stromal hypermethylation (Confirm MDx), as well as urinary assays for ERG (MiPS, ExoDx) and PCA3 in the decision to perform TRUS biopsy.
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Significant coagulopathy, severe immunosuppression, and acute prostatitis are all contraindications to prostate biopsy.
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Antibiotic choice for prophylaxis is best guided by knowledge of local antibiotic resistance patterns. Refer to recent AUA guidelines on antimicrobial prophylaxis for more detail.
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Extended 12-core systematic biopsy incorporating apical and far-lateral cores in the template distribution allows maximal cancer detection and avoidance of a repeat biopsy while minimizing the detection of insignificant prostate cancers.
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Fewer than 12 cores constitutes undersampling and an inadequate biopsy.
Risks and complications of biopsy
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Bleeding is the most common complication seen after prostate biopsy. Hematuria, hematochezia, and hematospermia should be expected.
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Urinary retention is a rare occurrence.
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Infection ranging from cystitis and orchitis to sepsis is the most serious side effect of biopsy and antibiotic prophylaxis and early identification and treatment of postbiopsy infection is critical.
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The AUA white paper on the prevention and treatment of common biopsy complications provides details on the frequency of complications ( Fig. 22.5 ).
Fig. 22.5
AUA White Paper: The prevention and treatment of the more common complications related to prostate biopsy update. https://www.auanet.org/guidelines/prostate-needle-biopsy-complications .
Pathology
Staging classification
The clinical staging of prostate cancer uses pretreatment parameters to predict the extent of disease, both for assessment of prognosis and to inform decisions regarding appropriate treatment ( Fig. 22.6 ). Clinical staging is the assessment of disease extent using pretreatment parameters (DRE, PSA values, needle biopsy findings, and radiologic imaging), whereas pathologic stage is determined after prostate removal and involves histologic analysis of the prostate, seminal vesicles, and pelvic lymph nodes if lymphadenectomy is performed.
Grading on prostate biopsy
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Architectural patterns are identified and assigned a grade from 1 to 5, with the most common and highest-grade patterns on a given core added to result in the Gleason score.
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See Box 22.1 for grade group definitions.
Box 22.1
Grade Group Definitions
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Grade group 1 (Gleason score 3 + 3 = 6): only individual discrete well-formed glands
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Grade group 2 (Gleason score 3 + 4 = 7): predominantly well-formed glands with lesser component of poorly formed, fused, cribriform glands
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Grade group 3 (Gleason score 4 + 3 = 7): predominantly poorly formed, fused, cribriform glands with lesser component of well-formed glands
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Grade group 4 (Gleason score 8)
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Poorly formed, fused, cribriform glands or
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Predominantly well-formed glands and any lesser component lacking glands
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Predominantly lacking glands and second most common component of well-formed glands
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Grade group 5 (Gleason scores 9 and 10): lack gland formation (or with necrosis) with or without poorly formed, fused, cribriform glands
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A tertiary (third) grade pattern is recorded typically when there is a nodule with Gleason score 3 + 4 = 7 or 4 + 3 = 7 and a minor (<5%) component of Gleason pattern 5.
High-grade prostatic intraepithelial neoplasia
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For patients diagnosed with unifocal high-grade prostatic intraepithelial neoplasia on extended initial core sampling, a repeat biopsy within the first year is unnecessary in the absence of other clinical indicators of cancer.
Imaging of the prostate
Multiparametric magnetic resonance imaging of the prostate
The Prostate Image Reporting and Data System (PIRADS) categorization represents a consensus opinion to allow the systematic evaluation of lesions detected on multiparametric magnetic resonance imaging (mpMRI) to estimate their potential risk for prostate cancer. PIRADS is a standardized lexicon for reporting the results of these examinations while maintaining the Likert scale from 1 to 5 ( Box 22.2 ).
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The PRECISION trial, a multicenter trial in Europe and North America, found that MRI-targeted biopsy had a higher detection rate of clinically significant disease and lower detection rate of clinically insignificant disease compared with standard transrectal ultrasound (TRUS) biopsy.
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