4.3 Histopathological Grading (ISUP Gleason) & Staging

Histopathological Grading (ISUP Gleason) & Staging

Accurate oncological staging and histopathological grading form the cornerstone of clinical decision-making in prostate cancer. Following tissue acquisition via targeted biopsy with perilesional sampling or systematic biopsy, precise risk stratification dictates whether a patient is a candidate for active surveillance, nerve-sparing radical prostatectomy, dose-escalated radiotherapy with androgen deprivation therapy, or multimodal systemic therapy.

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The Evolution of Histopathological Grading: From Gleason to ISUP Grade Groups

In 1966, Donald Gleason devised a histological grading system based solely on glandular architectural patterns (patterns 1 through 5) under low-power magnification, deliberately ignoring cytological atypia. The classical Gleason Score was generated by summing the primary (most prevalent) pattern and secondary (second most prevalent) pattern, creating a theoretical score ranging from 2 to 10.

Over subsequent decades, major revisions by the International Society of Urological Pathology (ISUP) in 2005 and 2014 fundamentally altered prostate cancer grading:

• Patterns 1 and 2 are not assigned in contemporary needle biopsy reporting; modern assessment uses patterns3–5.
• Ill-defined glands, fused glands, and cribriform architectures were reclassified definitively as Gleason Pattern 4.
• Consequently, the lowest score assigned on needle biopsy became Gleason 3+3=6.

The 2014/2016 ISUP Grade Group Classification

Reporting Gleason score 6 on a scale of 2 to 10 created substantial psychological distress for patients, who intuitively believed they had an intermediate, mid-tier cancer. Moreover, the historical Gleason 7 designation failed to distinguish between tumors dominated by low-grade glands (Gleason 3+4=7) versus those dominated by aggressive pattern 4 glands (Gleason 4+3=7).

To resolve these limitations, ISUP established the ISUP Grade Group system (subsequently endorsed by the World Health Organization [WHO] in 2016 and 2022):

ISUP GRADE GROUP CLASSIFICATION
├── Grade Group 1  ──> Gleason 3+3 = 6   (Indolent, discrete glands; ~0% metastatic potential)
├── Grade Group 2  ──> Gleason 3+4 = 7   (Predominantly pattern 3 with <50% pattern 4)
├── Grade Group 3  ──> Gleason 4+3 = 7   (Predominantly pattern 4 with >50% pattern 4)
├── Grade Group 4  ──> Gleason 8         (4+4, 3+5, or 5+3; high-risk biology)
└── Grade Group 5  ──> Gleason 9–10      (4+5, 5+4, or 5+5; dedifferentiated sheets/comedonecrosis)

Key Pathological Distinctions Between Grade Groups

• ISUP Grade Group 1 (Gleason 3+3=6): Composed purely of discrete, well-formed, individual malignant glands. It carries essentially zero potential for lymph node or distant metastasis when strictly organ-confined. Patients with Grade Group 1 disease are the primary candidates for active surveillance.
• ISUP Grade Group 2 (Gleason 3+4=7) vs. ISUP Grade Group 3 (Gleason 4+3=7): This distinction represents a critical clinical pivot point. While both sum to 7, Grade Group 3 harbors a predominance (>50%) of high-grade pattern 4 glands. Patients with Grade Group 3 exhibit a 2- to 3-fold higher rate of biochemical recurrence, a significantly shorter metastasis-free survival, and an increased risk of cancer-specific death compared to Grade Group 2.
• Minor Higher-Grade Patterns: Specimen type matters. On needle biopsy, incorporate a minor higher-grade component into the score; when three patterns are present, combine the most prevalent with the highest, irrespective of its amount. A core with predominant pattern3, pattern4 and <5% pattern5 is 3+5=8 (GG4). In a prostatectomy with predominant patterns3 and4, a minor pattern5 below5% can instead be reported separately alongside 3+4=7.

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Critical Adverse Histological Variants: Cribriform Pattern & IDC-P

Beyond basic Grade Group assignment, pathology reports must evaluate two adverse architectural entities that carry profound clinical implications:

1. Large Cribriform Architecture (Gleason Pattern 4)

Cribriform pattern 4 is characterized by solid islands of malignant epithelial cells perforated by multiple, well-delineated, rounded lumina without intervening stroma, resembling a perforated sieve:

• Molecular Biology: Strongly correlated with genomic instability, characterized by frequent PTEN deletion, SPOP mutations, and high genomic copy number alterations.
• Clinical Impact: Independent predictor of post-prostatectomy biochemical recurrence, bone metastasis, and cancer-specific mortality. Its presence, even in low-volume Grade Group 2 disease, is an EAU exclusion criterion for active surveillance when identified on biopsy (strong recommendation).

2. Intraductal Carcinoma of the Prostate (IDC-P)

IDC-P is defined by the malignant proliferation of high-grade neoplastic epithelial cells within pre-existing, native prostatic acini and ducts, with preservation of the underlying basal cell layer (demonstrated immunohistochemically by p63 or high-molecular-weight cytokeratin [HMWCK] positivity):

• Morphology: Displays marked nuclear enlargement (at least 6-fold larger than normal), solid or dense cribriform architecture, and characteristic central comedonecrosis.
• Distinction from High-Grade Prostatic Intraepithelial Neoplasia (HGPIN): HGPIN also retains basal cells, but lacks marked ductal expansion, dense cribriform architecture, and comedonecrosis. HGPIN on biopsy does not alter treatment pathways, whereas IDC-P represents retrograde intraductal spread of advanced, highly dedifferentiated invasive carcinoma.
• Genomic & Therapeutic Significance: Strongly associated with germline and somatic mutations in DNA homologous recombination repair (HRR) genes, predominantly BRCA2, ATM, and CDK12. Patients harboring IDC-P experience rapid progression to castration resistance and poor survival. Active surveillance is strictly contraindicated in the presence of IDC-P.

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TNM Staging Classification (UICC / AJCC 8th Edition)

The current EAU guideline uses TNM8. Clinical T-stage is based on DRE, with MRI findings reported separately. Pathological stage is determined from the surgical specimen; do not substitute microscopic pathological findings into a clinical T-category.

Primary Tumor (T Category)

• cT1: Clinically inapparent, non-palpable tumor:
  • cT1a: Tumor incidental histological finding in <= 5% of tissue resected (e.g., transurethral resection of prostate [TURP] for BPH).
  • cT1b: Tumor incidental histological finding in > 5% of tissue resected.
  • cT1c: Tumor identified by needle biopsy prompted by elevated serum PSA.
• cT2: Palpable tumor confined within the prostate:
  • cT2a: Involves one-half of one lobe or less.
  • cT2b: Involves more than one-half of one lobe, but not both lobes.
  • cT2c: Involves both prostatic lobes.
• cT3: Tumor extends palpably through the prostatic capsule (locally advanced):
  • cT3a: Palpable extracapsular extension (unilateral or bilateral).
  • cT3b: Tumor invades one or both seminal vesicles.
• cT4: Tumor is fixed or invades adjacent anatomical structures other than seminal vesicles: external sphincter, rectum, levator ani muscles, or pelvic wall.

Pathological distinction: Organ-confined cancer after prostatectomy is pT2, without pT2a/b/c substages. Extraprostatic extension or microscopic bladder-neck invasion is pT3a; seminal-vesicle invasion is pT3b.

Regional Lymph Nodes (N Category)

Regional lymph nodes are defined strictly as nodes situated within the true pelvis below the bifurcation of the common iliac arteries:

• Hypogastric (internal iliac)
• Obturator
• External iliac
• Presacral and sacral promontory nodes

LYMPH NODE METASTASIS CATEGORIZATION
├── Below Common Iliac Bifurcation (Internal/External Iliac, Obturator, Presacral) ──> N1 (Regional)
└── Non-regional (Common Iliac, Retroperitoneal/Para-aortic, Inguinal)          ──> M1a (Distant)

Distant Metastasis (M Category)

• M0: No distant metastasis.
• M1: Distant metastasis present:
  • M1a: Non-regional lymph node metastasis (common iliac, retroperitoneal, mediastinal, supraclavicular).
  • M1b: Bone metastasis (most common distant site; classically osteoblastic / sclerotic).
  • M1c: Other distant anatomical sites with or without bone disease (lung, liver, brain, adrenal glands).

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EAU Risk Stratification for Localized Prostate Cancer

Use the EAU2026 Table4.3 definitions. Localized groups apply within cT1–2; clinical T-stage comes from DRE. A higher-risk PSA or grade takes precedence:

EAU2026 RISK GROUPS
├── LOW: GG1 AND PSA <10 AND cT1–2
├── FAVOURABLE INTERMEDIATE: cT1–2, with either
│   ├── GG2 AND PSA <10
│   └── GG1 AND PSA 10–20
├── UNFAVOURABLE INTERMEDIATE: cT1–2, PSA <=20, with either
│   ├── GG2 AND PSA 10–20
│   └── GG3
├── HIGH LOCALIZED: GG4–5 OR PSA >20, with cT1–2
└── LOCALLY ADVANCED: cT3–4 and/or cN+, any PSA or GG

• Low Risk: GG1, PSA<10 and cT1–2. Assess surveillance or watchful waiting according to life expectancy and other clinical factors.
• Intermediate Risk: Distinguish favourable GG2/PSA<10 or GG1/PSA10–20 from unfavourable GG2/PSA10–20 or GG3. These are EAU definitions; a positive-core percentage rule from another classification should not be substituted for them.
• High Risk: PSA>20 or GG4–5. cT2c alone is no longer an independent high-risk criterion in the current table. It remains an organ-confined clinical stage.
• Locally Advanced: cT3–4 and/or regional nodal involvement, regardless of PSA or grade. Risk grouping helps guide management but does not assign a universal five-year metastasis probability to every patient.

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Primary Staging Modalities and Molecular Imaging Evidence

The necessity for systemic metastatic staging depends on the assigned EAU risk group:

Staging Guidelines by Risk Category

• Low-Risk and Favourable Intermediate-Risk Disease: EAU strongly recommends no routine additional staging imaging. This concerns metastatic screening, not the pre-biopsy MRI already used for diagnosis/local information.
• Unfavourable Intermediate Risk: Offer PSMA-PET/CT if available, or at least cross-sectional abdominopelvic imaging plus a bone scan (weak recommendation).
• High-Risk Localized or Locally Advanced Disease: Perform metastatic screening with PSMA-PET/CT if available, or at least cross-sectional abdominopelvic imaging and bone scintigraphy (strong recommendation).

Conventional Imaging vs. PSMA-PET/CT

• Conventional Staging: Consists of contrast-enhanced CT of the abdomen/pelvis (or mpMRI of the pelvis) combined with whole-body technetium-99m (99mTc) bone scintigraphy. Conventional CT relies purely on anatomical size criteria (short-axis nodal diameter >= 8–10 mm) and has poor sensitivity (35–40%) for micrometastatic nodal disease. Bone scans detect osteoblastic remodeling, exhibiting high false-positive rates from trauma, arthritis, and degenerative joint disease.
• Prostate-Specific Membrane Antigen (PSMA) PET/CT: PSMA is a 750-amino acid type II transmembrane glycoprotein overexpressed 100- to 1,000-fold in >90% of prostate adenocarcinomas. Positron emission tomography using radiolabeled small-molecule PSMA ligands—primarily Gallium-68 (68Ga-PSMA-11) and Fluorine-18 (18F-DCFPyL / 18F-PSMA-1007)—improves detection of nodal and distant disease. Small metastases below PET resolution can still be missed; a negative scan does not exclude microscopic nodal involvement.

Landmark Staging Evidence: The proPSMA Trial (Lancet 2020)

The prospective, multicentre randomized proPSMA study evaluated 302 patients with newly diagnosed high-risk localized prostate cancer scheduled for curative-intent surgery or radiation. Patients were randomized 1:1 to either conventional imaging (contrast CT + bone scan) versus 68Ga-PSMA-11 PET/CT:

• Diagnostic Accuracy: PSMA-PET/CT demonstrated 27% greater absolute accuracy than conventional imaging (92% vs 65%, p < 0.0001) for detecting pelvic nodal and distant metastases.
• Sensitivity and Specificity: PSMA-PET/CT showed vastly superior sensitivity (85% vs 38%) and higher specificity (98% vs 91%).
• Radiation Dose: PSMA-PET/CT delivered less than half the radiation exposure of conventional imaging (8.4 mSv vs 19.2 mSv).
• Equivocal Findings: Equivocal or uncertain imaging reports were significantly reduced (7% with PSMA-PET vs 23% with conventional imaging).
• Treatment Impact: First-line imaging changed planned management in 28% with PSMA-PET/CT versus 15% with conventional imaging. This establishes an effect on treatment planning, not proof that every imaging-driven change improves survival.

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EAU Risk Groups Classification for Localized Prostate Cancer