BY DR. JOHN SHUMWAY
Who Is at Risk for Prostate Cancer?
Prostate cancer is the most commonly diagnosed cancer in men in the U.S., with over 165,000 new cases annually and more than 1.2 million cases worldwide. Although many men do not die from it, it is the second leading cause of cancer-related death among American men. In 2015, around 3.1 million men in the U.S. were living with prostate cancer. Due to its high incidence, prolonged disease course, and treatment-related side effects, it contributes significantly to years lived with disability globally.
The median age at diagnosis is 66. Autopsy studies show early onset in some men: about 10% in their 20s and over 25% in their 40s may harbor undiagnosed prostate cancer. Most elderly men, especially over 80, will have some form of prostate cancer, typically low-grade and indolent. In contrast, men under 45 account for just 0.5% of new diagnoses. Most prostate cancer deaths occur in men over 75; only about 10% occur in those under 65.
Racial disparities exist: Black men are 1.7 times more likely to be diagnosed and 2.2 times more likely to die from prostate cancer than white men, despite undergoing less PSA screening and having reduced access to healthcare. Social determinants like delayed diagnosis and unequal treatment contribute to these outcomes. Asian-American men are less likely to be diagnosed or die from prostate cancer compared to white men.
Additional risk factors include age, race, a Western diet, obesity, and potentially diabetes. 5-alpha reductase inhibitors can reduce prostate cancer risk but may be linked to more aggressive forms. About 10% of prostate cancers are hereditary, with BRCA2 and other DNA repair gene mutations increasing susceptibility. Genetic screening is now recommended in certain newly diagnosed cases based on family history and disease stage.
The Prostate Gland
The prostate is a small, ~30cc gland in the male pelvis, located below the bladder and surrounding the urethra. Its main role is producing fluid that supports sperm motility and makes up most of the ejaculate. It is regulated by testosterone and dihydrotestosterone (DHT).
The prostate consists of three main zones: peripheral (70%), central (25%), and transitional (5%). Most cancers arise in the peripheral zone, which is accessible via digital rectal exam and transrectal ultrasound-guided biopsy. The prostate is encased in a fibrous capsule, and its anterior region is composed of fibromuscular stroma.
Types of Prostate Cancer
According to the 2016 WHO classification, prostate cancer includes over 10 histologic types, with acinar adenocarcinoma being the most common. This type often expresses PSA, PSMA, and androgen receptors. Other forms include ductal adenocarcinoma, urothelial carcinoma, neuroendocrine tumors, and rare mesenchymal or hematopoietic tumors.
Intraductal carcinoma, distinct from ductal adenocarcinoma, is linked to worse outcomes and genetic abnormalities like BRCA2 mutations and PTEN loss. Neuroendocrine prostate cancers are rare and aggressive, especially the pure small-cell type, which lacks typical prostate markers but shows neuroendocrine differentiation.
What Do Gleason Grades Mean?
Prostate adenocarcinoma is graded using the Gleason system, which assesses how abnormal the cancer cells appear under a microscope. The pathologist assigns two numbers, each from 1 to 5, based on the most common and second most common growth patterns seen in the tumor tissue. These two numbers are added to produce the Gleason score (e.g., 3+4=7).
To simplify interpretation and better predict outcomes, this system has been refined into the ISUP Grade Groups (1 through 5):
- Grade Group 1 (Gleason ≤6): Low-risk, well-differentiated cancer
- Grade Group 2–3 (Gleason 7): Intermediate-risk cancer
- Grade Group 4–5 (Gleason 8–10): High-risk, poorly differentiated or aggressive cancer
Higher grade groups indicate a greater risk of tumor spread, recurrence, and worse prognosis. The Gleason and ISUP grades are essential tools for treatment decisions, including whether a patient might need active surveillance, surgery, or radiation.
| Gleason Score | Grade Group |
|---|---|
| 6 | 1 |
| 3 + 4 = 7 | 2 |
| 4 + 3 = 7 | 3 |
| 8 | 4 |
| 9–10 | 5 |
How Is Prostate Cancer Diagnosed?
Diagnosis requires tissue confirmation, typically prompted by an elevated prostate-specific antigen (PSA) level. A PSA ≥3 ng/mL warrants further evaluation, including repeat testing, digital rectal exam (DRE), and consideration of benign causes like infection or prostatitis.
PSA findings are combined with DRE, PSA density, and other risk factors to estimate cancer likelihood. Several blood and urine-based biomarkers assist in this process. The Prostate Health Index and the PCA3 test are FDA-approved tools to refine cancer risk assessment and biopsy decisions. Additional tests like the 4Kscore and Mi-Prostate Score evaluate the risk of aggressive cancer (Gleason ≥7).
Multiparametric MRI has improved the detection of clinically significant cancers while reducing unnecessary biopsies. Combining systematic (templated) and MRI-targeted biopsies enhances detection, as either method alone may miss cancers. Biopsy is typically done via transrectal ultrasound with at least 12 cores.
Prostate cancer can also be found incidentally during surgeries like transurethral resection of the prostate (TURP) or cystoprostatectomy.
Prostate Cancer Stages and Risk Grouping
After diagnosis, staging depends on PSA level, grade group, and TNM classification. Prostate cancer is categorized as localized, locally advanced, node-positive, or metastatic.
While the AJCC TNM system is used for basic staging, most clinicians rely on the NCCN risk stratification system, which divides patients into six categories: very low, low, favorable intermediate, unfavorable intermediate, high, and very high risk. This system helps guide treatment decisions and is based on clinical data rather than consensus alone.
Other tools include the CAPRA score, which incorporates age, PSA, Gleason score, and percent of positive biopsy cores. Post-surgical staging can be assessed using CAPRA-S. Online nomograms, such as those from Memorial Sloan Kettering, are commonly used to predict individual prognosis.
Newer genomic classifiers like Decipher provide more detailed risk assessments by identifying patients within each NCCN group who may be at higher risk of recurrence or metastasis. These tests are now covered by Medicare and are undergoing prospective validation.
Primary Tumor: Clinical (cT) vs Pathologic (pT)
The TNM system is used to stage prostate cancer, with the “T” referring to the size and extent of the primary tumor. Staging can be either clinical (cT) or pathologic (pT).
Clinical staging (cT) is based on findings from the digital rectal exam, imaging, and biopsy results before any treatment is given. Pathologic staging (pT), on the other hand, is determined after surgical removal of the prostate and reflects a more definitive assessment of tumor spread. Understanding the difference between cT and pT stages is essential for treatment planning and evaluating disease progression.
In the TNM staging system, the T category (Primary Tumor) describes how far the prostate cancer has grown in and around the prostate. Here’s a breakdown of what each T stage means, covering both clinical (cT) and pathologic (pT) categories:
| Stage | Clinical (cT) | Pathologic (pT) |
|---|---|---|
| T1 | Clinically inapparent tumor; neither palpable nor visible by imaging | |
| – T1a | Incidental histologic finding in <5% of tissue resected | Same as clinical |
| – T1b | Incidental histologic finding in >5% of tissue resected | Same as clinical |
| – T1c | Identified by needle biopsy (e.g., due to elevated PSA) | Same as clinical |
| T2 | Palpable and confined within prostate | Organ-confined |
| – T2a | Involves one half of one side or less | Same as clinical |
| – T2b | Involves more than one half of one side, but not both sides | Same as clinical |
| – T2c | Involves both sides | Same as clinical |
| T3 | Extraprostatic tumor, not fixed, no invasion of adjacent structures | Extraprostatic extension |
| – T3a | Extracapsular extension (unilateral or bilateral) | Extraprostatic extension or microscopic invasion of bladder neck |
| – T3b | Invades seminal vesicles | Invades seminal vesicle(s) |
| T4 | Fixed or invades adjacent structures (except seminal vesicles): bladder, external sphincter, rectum, levator muscles, pelvic wall | Same as clinical |
Regional Lymph Nodes (N)
In prostate cancer staging, regional lymph nodes are the pelvic lymph nodes most commonly evaluated for cancer spread. These nodes are considered part of the N category in the TNM system.
| Stage | Definition |
|---|---|
| N0 | No regional lymph node involvement |
| N1 | Regional lymph node involvement present |
Involvement of these nodes (N1) indicates regional spread and may influence treatment decisions such as adding radiation or systemic therapy. The following are classified as regional lymph nodes:
- Pelvic
- Hypogastric
- Obturator
- Iliac (internal, external)
- Sacral
Distant Metastasis (M)
The M category in prostate cancer staging refers to distant metastasis, meaning the cancer has spread beyond the prostate and regional lymph nodes to distant parts of the body. When prostate cancer spreads to distant lymph nodes, it is classified as M1a, while spread to bones (M1b) or other organs (M1c) represents more advanced disease. Identifying distant lymph node involvement is crucial for staging accuracy and typically requires advanced imaging techniques.
| Stage | Definition |
|---|---|
| M0 | No distant metastasis |
| M1a | Non-regional lymph nodes |
| M1b | Bone metastases |
| M1c | Other distant sites |
The following lymph nodes are considered distant in prostate cancer staging:
- Aortic
- Common iliac
- Inguinal (deep and superficial/femoral)
- Supraclavicular
- Cervical
- Scalene
- Retroperitoneal
NCCN Risk Groups
To help guide treatment decisions, prostate cancer is also categorized into risk groups based on clinical features such as PSA level, Gleason score, and clinical T stage. The National Comprehensive Cancer Network (NCCN) defines these risk groups to estimate the likelihood of disease progression or recurrence and to tailor treatment accordingly. Patients are classified into very low, low, intermediate (favorable or unfavorable), high, or very high risk — each with specific implications for management.
| Risk Group | Subgroup | PSA (ng/mL) | T-stage | Grade Group | Other Factors |
|---|---|---|---|---|---|
| Low | Very Low | <10 | cT1c | 1 | – ≤3 biopsy cores positive – ≤50% cancer in each core – PSA density <0.15 |
| Low | <10 | cT1–T2a | 1 | Doesn’t meet very low criteria | |
| Intermediate | Favorable | 10–20 | cT2b–c | 2 | – Only 1 intermediate risk factor – Percent positive cores <50% |
| Unfavorable | 10–20 | cT2b–c | 2–3 | – Doesn’t meet favorable intermediate risk criteria – Grade group 3 – ≥2 intermediate risk factors – 1 intermediate risk factor and ≥50% positive cores |
|
| High | High | >20 | cT3a | 4 | At least 1 high risk feature |
| Very High | >40 | cT3b–T4 | 4–5 | At least 2 very high risk features | |
| Advanced | Node Positive | – | – | – | Regional node positive |
| Metastatic | – | – | – | Distant metastasis |
Overall staging
Once the TNM stage, Gleason grade, and PSA level are determined, they are combined to assign an overall stage grouping (Stages I–IV). These stages provide a simplified summary of the cancer’s extent and help guide prognosis and treatment planning. Early-stage cancers (Stage I–II) are usually confined to the prostate, while more advanced stages (III–IV) indicate local extension, lymph node involvement, or distant metastasis.
| AJCC 8th Edition Stage | Grade Group | NCCN Risk Group | Features |
|---|---|---|---|
| I | 1 | Low | cT1–T2aN0M0 and PSA < 10 |
| IIA | 1 | Intermediate | cT1–T2aN0M0 and PSA 10–20 or cT2b–cN0M0 and PSA < 20 |
| IIB | 2 | Intermediate | cT1–T2N0M0 and PSA < 20 |
| IIC | 3 | Intermediate | cT1–T2N0M0 and PSA < 20 |
| – | 4 | High | cT1–T2N0M0 and PSA < 20 |
| IIIA | 1–4 | High | cT1–T2N0M0 and PSA > 20 |
| IIIB | 1–4 | Very High | cT3–T4N0M0 |
| IIIC | 5 | High | N0M0 |
| IVA | – | Node Positive | N1 |
| IVB | – | Metastatic | M1 |