Prostate Carcinoma: Revised Gleason Scoring and Prognostic Markers

Introduction

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 906

Pathogenesis: Key Molecular Events

1. TMPRSS2:ERG gene fusion - present in 50-60% of localized prostate cancers; brings ETS family oncogenic transcription factors under androgen control. An early and seminal event, found in HGPIN and early-stage cancer.
2. GSTP1 hypermethylation - impairs detoxification of polycyclic aromatic hydrocarbons.
3. PTEN loss - cooperates with TMPRSS2:ERG fusions to drive early tumor progression.
4. p27 (CDKN1B) loss - transition from HGPIN to localized adenocarcinoma.
5. TP53, RB mutations + MYC amplification - castration-resistant, aggressive stage.

Precursor Lesion: High-Grade PIN (HGPIN)

• Prostatic intraepithelial neoplasia (PIN) consists of architecturally benign acini or ducts lined by cytologically atypical cells.
• HGPIN is found in ~80% of radical prostatectomy specimens that also harbor carcinoma.
• It shares genetic alterations with invasive carcinoma (TMPRSS2:ERG fusions, telomere shortening).
• HGPIN alone on needle biopsy carries a lower risk of subsequent cancer detection than previously thought; rebiopsy is not mandatory unless risk factors are present.

Morphology

Gross

• 70% arise in the peripheral zone (posterior), making them palpable on digital rectal examination.
• Cut surface: gritty, firm gray-white tissue.
• Sometimes difficult to delineate from surrounding stroma.

Microscopy (Acinar Adenocarcinoma)

The Gleason Grading System (Original and Revised)

Original Gleason System

• Because prostate cancer is heterogeneous, a primary grade (dominant pattern) and a secondary grade (second most frequent pattern) are assigned.
• Gleason Score = Primary grade + Secondary grade (range: 2-10).
• Scores ≤6: low risk; 7: intermediate; 8-10: high risk.

ISUP 2005 Revised Gleason System

1. Grades 1 and 2 are no longer assigned on needle biopsies - their biologic behavior is similar to Grade 3, creating overgrading confusion; minimum score on biopsy is now 6 (3+3).
2. Grade 3 redefined: Only well-formed discrete, individual glands (no longer includes cribriform glands).
3. Cribriform and poorly formed glands reassigned to Grade 4 (cribriform = adverse histology).
4. Tertiary pattern: When a tertiary (third) pattern is present in radical prostatectomy, the highest grade replaces the secondary grade in the score (e.g., 3+4 with tertiary 5 becomes effectively higher risk).
5. Gleason scores 2-5 eliminated from clinical reporting.

ISUP 2014/WHO 2016 Grade Groups (Epstein et al.)

• GG 1 (Gleason score ≤6): Essentially no metastatic potential - suitable for active surveillance.
• The 3+4 vs 4+3 distinction is prognostically significant - a 4+3 (GG3) behaves significantly worse.
• Grade Group is now used alongside TNM staging to generate combined prognostic stage groups (AJCC 8th edition).
• Patients with GG1 previously labeled "cancer" were experiencing unnecessary psychological harm and overtreatment - renaming as "Grade Group 1" helps communicate the indolent nature.

Pathologic Staging (pTNM)

• pT2: Organ-confined
• pT3a: Extraprostatic extension
• pT3b: Seminal vesicle invasion
• pT4: Invasion of bladder, rectum, or adjacent structures
• N1: Regional lymph node (obturator, paraaortic) metastasis
• M1: Bone metastases (characteristically osteoblastic - distinguishes from most other bone metastases)

Prognostic Markers

Established Prognostic Factors

• Kallikrein family serine protease; normally liquefies seminal coagulum.
• Elevated in cancer, BPH, prostatitis, and infarction - organ-specific but NOT cancer-specific.
• Suboptimal screening specificity, but serial PSA after treatment is highly valuable for monitoring recurrence.
• PSA density (PSA/prostate volume) and PSA velocity (rate of rise) improve specificity.
• % free PSA: Lower free/total PSA ratio is associated with higher probability of cancer.

Molecular/Immunohistochemical Prognostic Markers

• Present in 50-60% of prostate cancers.
• Associated with higher risk for prostate cancer-specific death in men on watchful waiting (some studies), though data are mixed in surgical series.

• Tumor suppressor loss activates PI3K/Akt pathway.
• Detected by FISH or IHC; associated with higher grade, extraprostatic extension, and worse prognosis.
• ETS fusions + PTEN loss together confer a more aggressive phenotype.

Genomic Classifiers (Newer Updates)

• Oncotype DX Genomic Prostate Score (GPS): 17-gene expression assay on biopsy tissue; predicts pathologic upgrade and adverse pathology in low/intermediate risk disease.
• Prolaris (cell-cycle progression score): 31-gene expression assay; predicts biochemical recurrence and prostate cancer-specific mortality.
• Decipher (GenomeDx): 22 RNA biomarkers; predicts metastasis after radical prostatectomy; validated in multiple cohorts.
• BRCA1/2, ATM mutations (HRR genes): Germline or somatic; predictive for benefit from PARP inhibitors (olaparib, rucaparib) in CRPC.

Adverse Histologic Features (2019 ISUP Update)

• Cribriform architecture in Grade 4: Associated with worse outcomes than non-cribriform Grade 4; should be reported separately.
• Intraductal carcinoma of the prostate (IDC-P): Distinct entity from HGPIN; associated with high-grade, high-stage cancers and worse biochemical recurrence. Should be reported regardless of invasive grade.
• Lymphovascular invasion: Independent predictor of metastasis.

Summary Table: Prognostic Risk Stratification

Key Points for Exam

1. Gleason score is PRIMARY grade + SECONDARY grade; range 2-10 (but in practice now 6-10 on biopsy).
2. 2005 ISUP revision abolished Grades 1 and 2 on biopsy; redefined Grade 3 (no cribriform); assigned cribriform to Grade 4.
3. Grade Groups (2014 ISUP/WHO 2016): GG1 (≤6) to GG5 (9-10) - better prognostic stratification.
4. GG1 tumors almost never metastasize; appropriate for active surveillance.
5. 3+4 (GG2) has better prognosis than 4+3 (GG3) even though both are Gleason score 7.
6. PSA: organ-specific, not cancer-specific; serial post-treatment PSA is gold standard for monitoring.
7. AMACR positive + basal cell markers (p63, CK5/14) absent = diagnostic of adenocarcinoma.
8. TMPRSS2:ERG fusion is the most common recurrent genetic alteration (50-60%).
9. PTEN loss + ETS fusion = more aggressive phenotype.
10. Cribriform Grade 4 and intraductal carcinoma (IDC-P) are adverse histologic features in 2019 ISUP update.
11. Bone metastases are characteristically osteoblastic - due to factors secreted by tumor cells that stimulate osteoblasts.
12. Genomic classifiers (Decipher, Prolaris, Oncotype DX GPS) add prognostic value beyond Gleason grade and PSA.

• Robbins, Cotran & Kumar Pathologic Basis of Disease (10th ed.), Chapter 21 (Male Genital System), pp. 906-910
• Bailey and Love's Short Practice of Surgery (28th ed.), Chapter 84 (Prostate), pp. 8828-8870
• Campbell-Walsh-Wein Urology, Chapters 83-84 (Molecular Biology and Pathology of Prostate Cancer)
• ISUP 2005 and 2014 Consensus Conferences (Epstein et al.)
• WHO Classification of Urinary and Male Genital Tumours, 5th ed. (2022)