Once a prostate adenocarcinoma has been diagnosed, saying "the patient has prostate cancer" is not enough to make a treatment decision. We need to answer at least three questions: how far has it spread? (TNM), how histologically aggressive is it? (ISUP Grade Group) and what is its risk of progression or recurrence? (risk classification). These three dimensions complement each other.
To initially build the risk of a prostate cancer we must integrate PSA + clinical stage + ISUP Grade Group. They should not be interpreted in isolation.
Example
A patient with PSA 6 + GG1 + cT1c does not have the same disease as another with PSA 52 + GG5 + cT3b, even though both share the same general histological diagnosis of prostatic adenocarcinoma.
TNM describes the anatomical extent of disease: T (primary tumor), N (regional lymph nodes) and M (distant metastasis). The system used in the teaching material is based on the UICC classification.
An important concept for the resident: cT is classically based on the digital rectal exam. If we are describing extension identified by MRI or another imaging method, we must specify it and not automatically mix clinical and imaging stage. This is particularly important when we later use risk systems built from clinical stage.
T1 = clinically non-palpable tumor. It is divided into:
Classic example
PSA 6.2, normal digital rectal exam, biopsy with adenocarcinoma → cT1c.
Tumor clinically confined to the prostate.
⚠️ Teaching pearl
Invasion of the prostatic apex or capsule without penetrating it does not make the tumor T3. It remains T2.
Here the tumor is no longer clinically confined to the prostate.
Seminal vesicle = T3b.
The tumor invades adjacent structures other than the seminal vesicles: external urethral sphincter, rectum, levator muscles or pelvic wall. T4 = invasion of adjacent structures.
N describes regional lymph node involvement. In prostate cancer we must distinguish regional from non-regional lymph nodes. This is important because an involved regional node corresponds to N+ disease, whereas certain distant nodes belong to the metastatic category.
Classically:
This anatomical classification remains fundamental even in the era of PSMA PET.
PSMA PET detects disease with higher sensitivity than many conventional studies. This creates an interesting situation: a patient previously classified as N0 M0 may have small lesions identifiable on PSMA PET. This produces stage migration.
When a more sensitive diagnostic technique reclassifies patients, an apparent prognostic improvement can occur in both groups. Patients with disease that previously remained hidden leave the apparently localized group and move to a higher-stage group. As a consequence, the lower-stage group is made up of patients who are truly more favorable, and the advanced group takes on patients with a lower disease volume who previously went undetected.
⚠️ Teaching pearl
This can apparently improve the outcomes of both groups without the individual biology of the disease necessarily having changed: the Will Rogers phenomenon. The teaching material uses this concept to explain the potential impact of molecular staging.
With the expansion of molecular imaging, specific systems were developed to standardize the interpretation of PSMA PET. One of them is PROMISE (Prostate Cancer Molecular Imaging Standardized Evaluation), which seeks to provide a structured nomenclature to describe the prostate tumor, lymph node involvement, bone disease, visceral metastases, and the distribution and volume of disease.
In the context of molecular imaging, molecular staging categories can be used. The material distinguishes, among others: regional lymph nodes (miN), non-regional lymph nodes (miM1a), bone (miM1b) and distant organs (miM1c). In bone disease, the distribution can also be described as single, oligometastatic, disseminated or diffuse bone marrow involvement.
An important teaching point: clinical TNM and miTNM are not interchangeable. If a classification comes from PSMA PET, it must be clear that we are talking about molecular staging. The material also emphasizes that these molecular classifications must still be interpreted taking into account their validation and their relationship to conventional systems.
The second major dimension is: how aggressive is the tumor? Tumor architecture is expressed by Gleason and, currently, ISUP Grade Group.
| Gleason | ISUP Grade Group |
|---|---|
| 3+3=6 | GG1 |
| 3+4=7 | GG2 |
| 4+3=7 | GG3 |
| 8 | GG4 |
| 9–10 | GG5 |
The higher the Grade Group, the greater the biological aggressiveness.
Both add up to 7. But in 3+4 pattern 3 predominates, whereas in 4+3 pattern 4 predominates.
Gleason 4+3 has a worse prognosis than 3+4. This difference explains why they belong to different Grade Groups.
Now we integrate PSA + cT + ISUP GG. Risk classification groups patients with relatively similar probabilities of progression/recurrence and guides treatment decisions. The teaching material derives it from the D'Amico-type risk classification and divides it into clinically useful groups.
Typical features: ISUP GG1 + PSA <10 ng/mL + cT1–T2. It represents the lowest-risk scenario within localized disease. These patients are especially important to consider for strategies such as active surveillance when they meet the other clinical criteria.
There is considerable heterogeneity within intermediate risk. We can conceptualize patients with favorable and unfavorable features.
⚠️ Teaching pearl
Not all intermediate risks behave the same way.
High-risk features include ISUP GG4–5 and/or PSA >20 ng/mL, depending on the combination of factors and the system used. These patients have a higher risk of recurrence, progression, nodal disease and metastatic disease. For this reason they need an appropriate extension work-up and often multimodal treatment strategies.
When we find cT3–T4 and/or cN+, we enter the scenario of locally advanced disease. Here it is particularly important not to simply call the patient "high risk": the anatomical extent has its own diagnostic and therapeutic implications.
There is also the Cambridge Prognostic Group (CPG), which integrates Grade Group, PSA and T stage, and divides non-metastatic disease into five prognostic groups. The material includes it for teaching purposes, making clear that it is presented as a complementary system and not as the main classification used in the guideline being taught.
We do not classify for academic reasons. We classify because risk changes treatment. Depending on the scenario, we may end up discussing active surveillance, radical prostatectomy, radiotherapy, hormonal therapy, multimodal strategies or systemic treatment.
Final concept
For every new diagnosis of prostate cancer, the resident should be able to answer three questions before discussing treatment: what is the extent? what is the histological aggressiveness? and which risk group does the patient belong to?
PDF pending upload.
Biopsy positive for adenocarcinoma:
1. HistologyGleason → ISUP Grade Group.
2. PSA 3. Clinical examDigital rectal exam → cT.
4. Imaging according to riskMRI ± nodal/metastatic staging ± PSMA PET as indicated.
5. TNMT + N + M.
6. Risk classificationPSA + cT + ISUP → low risk / intermediate risk / high risk / locally advanced / metastatic.
7. Choice of treatment5 common resident mistakes
58-year-old man. PSA: 5.8 ng/mL. Digital rectal exam: normal. Biopsy: 2/12 cores positive, Gleason 3+3=6. Bone imaging without lesions.
Step 1 — TNMNon-palpable tumor, diagnosed by biopsy prompted by PSA → cT1c. No nodal evidence → N0. No metastasis → M0. Result: cT1cN0M0.
Step 2 — ISUPGleason 3+3=6 → ISUP GG1.
Step 3 — RiskPSA <10 + GG1 + cT1 → low risk. The teaching material reaches this same classification and uses it as an example of CPG1.
66-year-old man. PSA: 10.34 ng/mL. Digital rectal exam: small nodule in the right lobe. Biopsy: Gleason 3+4=7, 3/14 cores positive. PSMA PET: prostatic uptake with no evidence of nodal involvement or distant metastasis.
TNMNodule limited to a small portion of one lobe → cT2aN0M0.
ISUPGleason 3+4 → GG2.
RiskWe are dealing with intermediate risk. Here begins a much more interesting clinical discussion than simply memorizing a table: disease volume, percentage of pattern 4, biopsy burden, MRI, PSA density and life expectancy can modify the subsequent treatment strategy. The case and its classification are developed in the original material.
74-year-old patient. PSA: 52 ng/mL. Digital rectal exam: fixed prostate. MRI: peripheral PI-RADS 5 lesion, extracapsular extension, left seminal vesicle invasion, external iliac lymphadenopathy. Biopsy: Gleason 4+5=9. PSMA PET: intensely avid prostatic lesion, extracapsular extension, seminal vesicle invasion, external iliac lymphadenopathy consistent with nodal involvement, no bone lesions.
TNMSeminal vesicle invasion → T3b. Regional lymph node involved → N1. No distant metastasis → M0. Result: cT3bN1M0.
ISUPGleason 4+5=9 → ISUP GG5.
ClassificationThis patient should not be described simply as localized high-risk cancer. He has locally advanced disease with regional lymph node involvement. The teaching material classifies the case as cT3bN1M0, GG5 and locally advanced.