Prostate Anatomy and Cancer-Vulnerable Cells
Anatomic Zones of the Prostate
The prostate gland consists of three distinct glandular zones with markedly different susceptibilities to malignant transformation: the peripheral zone (site of >70% of cancers), the central zone (relatively cancer-resistant), and the transition zone (primary site of benign hyperplasia but also 10-20% of cancers). 1, 2
Peripheral Zone
- Comprises over 70% of glandular prostate tissue and forms a disc-shaped structure whose ducts radiate laterally from the urethra distal to the verumontanum 2
- This zone is the primary site of origin for most prostate adenocarcinomas and prostatic intraepithelial neoplasia (PIN), which is considered a precursor lesion 1, 3
- Contains higher rates of cell proliferation and apoptosis compared to the central zone, which may explain increased cancer susceptibility 4
- Has significantly more neuroendocrine cells than the central zone, potentially contributing to its disease vulnerability 4
Central Zone
- Constitutes approximately 25% of glandular tissue with ducts arising near ejaculatory duct orifices 2
- Demonstrates remarkable resistance to carcinoma and other diseases due to distinct histologic and biologic features 1, 3
- Shows approximately 50% lower proliferative index and half the incidence of apoptotic cells compared to peripheral and transition zones 4
- Shares embryological features with seminal vesicles (possibly Wolffian duct origin), distinguishing it from other zones 4
Transition Zone
- Represents the smallest glandular component in young men but is the exclusive site of origin for benign prostatic hyperplasia (BPH) 1, 3, 2
- A subset of prostate cancers (10-20%) arises in this zone, most found incidentally at transurethral resection 3
- Contains atypical adenomatous hyperplasia (AAH), a morphological lesion that may provide a link between BPH and transition zone cancers 3
- Located in the preprostatic region proximal to the verumontanum, where duct development is limited by intimate relationship with periurethral smooth muscle sphincter 2
Anterior Fibromuscular Stroma
- Forms the entire anterior surface as a thick, nonglandular apron that is not a site of cancer origin 2
Most Vulnerable Cell Types to Mutations and Cancer
Secretory Epithelial Cells
The secretory epithelial cells lining ducts and acini in the peripheral zone are the primary cells that undergo malignant transformation in prostate cancer. 1
- These cells demonstrate higher proliferative activity in peripheral and transition zones compared to central zone 4
- The higher rate of cell turnover in peripheral and transition zones correlates with increased incidence of proliferative diseases including cancer 4
Basal Cell Layer Considerations
- All glandular zones contain a layer of basal cells beneath the secretory epithelium 1
- Loss or disruption of the basal cell layer is a hallmark of invasive adenocarcinoma, distinguishing it from benign conditions 1
Neuroendocrine Cells
- Interspersed throughout the epithelium, with significantly higher concentrations in the peripheral zone compared to central zone 4
- Absent from seminal vesicles, suggesting zone-specific distribution patterns 4
Genetic Vulnerability and Risk Factors
Hereditary Mutations Conferring Highest Risk
Men with BRCA2 germline mutations face 2-6 fold increased risk of prostate cancer and develop more aggressive disease, accounting for up to 2% of early-onset cases. 5, 6, 7
- Approximately 9% of prostate malignancies are due to inherited predisposition, with chromosomes 1,8,10,16,17,20, and X associated with prostate cancer 5, 7
- Men with one first-degree relative have 2.5-fold increased risk; two relatives confer 5-fold risk; three relatives result in 11-fold increased risk 5, 6
- Genetic analyses suggest autosomal dominant inheritance with 88% penetrance 5, 6
DNA Repair Gene Mutations
- 11.8% of men with metastatic prostate cancer harbor germline mutations in DNA repair genes, including BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), and BRCA1 (0.9%) 5
- In localized high-risk disease, 6% carry germline DNA repair mutations compared to 2% in low/intermediate risk disease 5
Lynch Syndrome
- Men with Lynch syndrome (MLH1, MSH2, MSH6, PMS2 mutations) have 2-5 fold increased prostate cancer risk 5
- Approximately 3.1% of prostate cancer patients demonstrate MSI-H/dMMR status, with 21.9% of these having Lynch syndrome 5
Intraductal and Ductal Histology
Prostate tumors with intraductal or ductal histology demonstrate increased genomic instability and are more likely to harbor somatic and germline MMR gene alterations. 5
- Intraductal histology is common in germline BRCA2 mutation carriers with prostate cancer 5
- Patients with intraductal carcinoma on biopsy should undergo germline testing regardless of other risk factors 5
Clinical Implications for Men Over 50 with Family History
Age-Related Risk
- More than 70% of prostate cancer patients are diagnosed after age 65, with median age at diagnosis of 71 years 5, 7
- A 50-year-old man has 42% lifetime chance of developing histological prostate cancer, 9.5% risk of clinically important disease, and 2.9% risk of death from prostate cancer 5
Screening Recommendations for High-Risk Men
Men at age 50 with family history should undergo annual PSA blood test and digital rectal examination, with consideration for starting at age 45 if multiple first-degree relatives affected or BRCA2 mutation present. 5, 6
- Men with BRCA2 mutations should begin screening at age 40-45 rather than age 50 5, 6
- Baseline PSA value is a stronger predictive factor than family history or race alone for determining screening intensity 5, 7
Germline Testing Indications
Men over 50 with family history and any of the following should undergo germline genetic testing: high-risk/very-high-risk/metastatic disease, Ashkenazi Jewish ancestry, or intraductal histology on biopsy. 5