Residency · Residency · Urology

Gleason Grading and Pathologic Risk Stratification

Overview

The Gleason grading system, including the Grade Group classification, plays a pivotal role in prostate cancer diagnosis and management. It emphasizes architectural patterns observed under low-to-medium magnification, without relying on cytologic features. Particular attention is given to the significance of cribriform patterns and intraductal carcinoma of the prostate (IDC-P), both of which carry important prognostic implications. Additionally, genomic classifiers such as Decipher, Oncotype DX, and Prolaris have emerged as valuable tools to refine risk stratification and guide treatment decisions, especially in cases where clinical and pathologic findings alone leave uncertainty.

Historical Background

The original Gleason grading system was developed by Donald Gleason in 1966 as part of the VA Cooperative Urological Research Group. This system was based solely on architectural patterns seen at low-to-medium magnification, deliberately excluding cytologic features. Gleason assigned patterns from 1 to 5 to the primary (most prevalent) and secondary (second most prevalent) tumor components, and the Gleason score was calculated by summing these two patterns, resulting in a range from 2 to 10. In 2005, the International Society of Urological Pathology (ISUP) modified the system by eliminating patterns 1 and 2 and refining the distinction between patterns 3 and 4. Later, in 2014, the ISUP introduced the Grade Group system, which categorizes prostate cancers into five groups based on Gleason scores, providing a more clinically relevant framework.

Gleason Patterns

Pattern 3

Gleason pattern 3 is characterized by individual, discrete, well-formed glands that vary in size but remain separate and infiltrate the surrounding tissue without merging. There is no gland fusion, cribriform architecture, or poorly formed glands present. This pattern is considered the "good" pattern due to its low metastatic potential, representing less aggressive disease.

Pattern 4

Pattern 4 includes several architectural subtypes: fused glands, where glands merge without intervening stroma; cribriform glands, which are large glandular structures containing multiple luminal spaces that give a sieve-like appearance; poorly formed glands that are irregular and barely recognizable as glandular; and glomeruloid structures, which are intraluminal projections resembling renal glomeruli. Pattern 4 marks a critical threshold because it is associated with a significantly increased risk of metastasis compared to pattern 3.

Pattern 5

Pattern 5 shows no glandular differentiation and is composed of solid sheets, cords, single cells, or areas of comedonecrosis, which is necrosis within solid tumor nests. This pattern carries the worst prognosis and is strongly linked to a high rate of metastasis.

ISUP Grade Groups (2014 / Confirmed 2019)

The ISUP Grade Group system classifies prostate cancer into five groups based on Gleason scores, reflecting the biological spectrum more accurately. Grade Group 1 corresponds to Gleason score 3+3=6 and has an excellent prognosis with very low metastatic risk. Grade Group 2 includes Gleason 3+4=7 and is associated with good outcomes and favorable intermediate risk. Grade Group 3, representing Gleason 4+3=7, has a moderate prognosis and is considered unfavorable intermediate risk. Grade Group 4 encompasses Gleason scores 4+4=8, 3+5=8, and 5+3=8, indicating poor prognosis. Finally, Grade Group 5 includes Gleason scores 4+5=9, 5+4=9, and 5+5=10, which carry the worst prognosis. This system eliminates the misleading impression that Gleason 6 is a mid-range cancer and supports patient counseling by emphasizing that Grade Group 1 represents the lowest grade, often suitable for active surveillance.

Cribriform Pattern Significance

The presence of cribriform architecture within Gleason pattern 4 is associated with a worse prognosis compared to other pattern 4 subtypes. It correlates with higher rates of biochemical recurrence, metastasis, and cancer-specific mortality. Large cribriform glands, defined as those with more than 12 lumina, are particularly aggressive. Due to its prognostic importance, some experts recommend reporting cribriform morphology separately. The detection of cribriform pattern may influence clinical decisions, potentially shifting management from active surveillance toward definitive treatment, especially in Grade Group 2 patients.

Intraductal Carcinoma of the Prostate (IDC-P)

Intraductal carcinoma of the prostate is a malignant epithelial proliferation confined within pre-existing prostatic ducts and acini, distinguished from invasive carcinoma by the retention of the basal cell layer. It is characterized by solid or dense cribriform growth, comedonecrosis, and marked nuclear pleomorphism. IDC-P is almost always found adjacent to high-grade invasive carcinoma, typically Gleason 4+4 or higher. It serves as an independent poor prognostic factor, associated with higher recurrence rates after radical prostatectomy and earlier development of castration-resistant disease. When IDC-P is identified on biopsy without concurrent invasive cancer, it strongly suggests the presence of unsampled high-grade cancer nearby and is not compatible with active surveillance. Therefore, IDC-P should be reported separately from the Gleason grade.

Tertiary Pattern

A tertiary Gleason pattern refers to a third pattern that occupies less than 5% of the tumor. It becomes clinically significant when this tertiary pattern is of higher grade than the primary and secondary patterns, for example, a tumor scored as 3+4=7 with a tertiary pattern 5. The presence of tertiary pattern 5 in radical prostatectomy specimens independently predicts biochemical recurrence. Pathologists should report tertiary patterns, as their presence may influence staging and management decisions.

NCCN Risk Stratification

The National Comprehensive Cancer Network (NCCN) risk stratification categorizes prostate cancer into several groups based on Grade Group, PSA level, clinical stage, and extent of disease. Very low risk includes Grade Group 1, PSA less than 10, clinical stage T1c, fewer than three positive biopsy cores, no more than 50% cancer involvement in any core, and PSA density below 0.15. Low risk comprises Grade Group 1, PSA less than 10, and clinical stage T1 to T2a. Favorable intermediate risk includes Grade Groups 1 to 2 with only one intermediate-risk factor, such as PSA between 10 and 20 or clinical stage T2b to T2c, with no more than one intermediate-risk factor and less than 50% positive cores. Unfavorable intermediate risk involves Grade Group 2 with more than one intermediate-risk factor, or Grade Group 3, or 50% or more positive cores. High risk includes Grade Groups 4 to 5, PSA greater than 20, or clinical stage T3a. Very high risk is defined by clinical stage T3b to T4, primary Gleason pattern 5, more than four cores with Grade Groups 4 to 5, or two to three high-risk features.

Genomic Classifiers

Genomic classifiers have become important adjuncts in prostate cancer risk assessment. Decipher, developed by GenomeDx, is a 22-gene RNA expression classifier performed on formalin-fixed paraffin-embedded tissue. It predicts the risk of metastasis at 5 and 10 years following prostatectomy. The Decipher score ranges from 0 to 1, with low risk defined as less than 0.45, intermediate risk between 0.45 and 0.60, and high risk above 0.60. It is used post-radical prostatectomy to guide decisions between adjuvant and salvage radiation and has also been validated on biopsy tissue to inform active surveillance decisions. The NCCN endorses Decipher for use in both post-prostatectomy and biopsy settings.

Oncotype DX Genomic Prostate Score (GPS) is a 17-gene assay performed on biopsy tissue that predicts adverse pathology at radical prostatectomy. The score ranges from 0 to 100 and is primarily used in Grade Groups 1 and 2 to help decide between active surveillance and treatment. It has been validated in very low, low, and favorable intermediate-risk groups.

Prolaris measures a 46-gene cell cycle progression (CCP) score, predicting prostate cancer-specific mortality. It can be applied to biopsy or prostatectomy tissue, and its score is often combined with clinical variables, such as the CAPRA score, to provide integrated risk assessment.

ProMark is a protein-based assay that evaluates eight protein biomarkers on biopsy tissue to predict non-favorable pathology at radical prostatectomy. However, it is less widely adopted compared to Decipher and Oncotype DX.

Pathologic Reporting Standards

Biopsy reports must include the Gleason score and Grade Group for each positive core, the number of positive cores out of total cores sampled, and the percentage of cancer involvement in each core. They should also document the presence or absence of perineural invasion, cribriform pattern, and intraductal carcinoma. The location of each core should be specified using sextant mapping.

Radical prostatectomy reports must provide the overall Gleason score and Grade Group, pathologic stage including pT and pN status, margin status with details on positivity, location, and linear extent, and whether extraprostatic extension is focal or established. Reports should also note seminal vesicle invasion, lymph node involvement with the number of positive nodes out of total examined, lymphovascular invasion, and the presence of any tertiary pattern. While tumor volume is optional, it is helpful for clinical decision-making.

<image>A comparison diagram of Gleason patterns 3, 4, and 5 showing representative histologic illustrations for each. Pattern 3 shows individual well-formed glands separated by stroma. Pattern 4 shows fused glands, cribriform structures, poorly formed glands, and glomeruloid bodies. Pattern 5 shows solid sheets, cords, single cells, and comedonecrosis. Each pattern is labeled with its defining features and relative prognosis. Clean medical illustration style with hematoxylin-and-eosin-like coloring.</image>

<image>A visual table mapping ISUP Grade Groups 1-5 to their corresponding Gleason scores with a color-coded risk gradient from green (Grade Group 1, low risk) to red (Grade Group 5, highest risk). Each row includes the Grade Group number, Gleason score combinations, 5-year biochemical recurrence-free survival rates, and metastatic potential. Side annotations show the NCCN risk categories and how Grade Groups map to them.</image>

<image>A flowchart for genomic classifier utilization in prostate cancer decision-making. Starting with initial biopsy pathology (GG1-3), branches show when to order Oncotype DX GPS (biopsy, low-favorable intermediate risk, active surveillance decision), Decipher (post-RP or biopsy, predicts metastasis to guide radiation), and Prolaris (biopsy or RP, predicts cancer-specific mortality). Each branch includes the clinical scenario, score interpretation ranges, and the management decision it informs. Professional clinical algorithm design.</image>

Clinical Pearls

Grade Group 1, corresponding to Gleason 3+3=6, has near-zero metastatic potential and is ideal for active surveillance in appropriate patients. It is important to counsel patients that this represents the lowest possible grade of prostate cancer. The distinction between 3+4 and 4+3 is clinically significant; although both sum to Gleason 7, Grade Group 2 (3+4) has substantially better outcomes than Grade Group 3 (4+3). The presence of cribriform pattern 4 and intraductal carcinoma on biopsy are red flags, as both independently predict worse outcomes and may shift management from surveillance toward active treatment. If IDC-P is found on biopsy without invasive cancer, a repeat biopsy or MRI-targeted biopsy is warranted because high-grade invasive disease is almost certainly present nearby. Earlier concerns that 5-alpha-reductase inhibitors cause grade inflation have been largely refuted. Genomic classifiers are most useful in the "gray zone" of decision-making, particularly in Grade Groups 1 to 2 and favorable intermediate risk, where the choice between surveillance and treatment is uncertain. Finally, pathology should always be reviewed with patients using Grade Group terminology, as it is more intuitive and less anxiety-provoking than describing Gleason 6 as "6 out of 10."

References

• Epstein JI, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2016;40(2):244-252
• Kweldam CF, et al. Cribriform growth is highly predictive for postoperative metastasis and disease-specific death in Gleason score 7 prostate cancer. Mod Pathol. 2015;28(3):457-464
• Spratt DE, et al. Individual patient-level meta-analysis of the performance of the Decipher genomic classifier. J Clin Oncol. 2017;35(18):1991-1998
• NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 4.2024
• Egevad L, et al. International Society of Urological Pathology (ISUP) grading of prostate cancer, 2019 update. APMIS. 2020;128(10):573-579

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