Understanding Gleason Grading System for Prostate Cancer

Introduction: Once the diagnosis of adenocarcinoma (cancer) is made, it is important to determine the histologic grade of the tumor – i.e. the degree of aggressiveness of the tumor. Low-grade tumors progress slowly whereas high-grade tumors grow rapidly and may have adverse outcome.

The histologic grade is assigned by observing the degree of differentiation of the tumor cells and glands – i.e. the extent to which tumor cells and glands formed by them resemble normal prostate cells and glands.

Well-differentiated cancers closely mimic the architecture of normal prostate glands. They are slow growing and less dangerous. Moderately-differentiated cancers show features and biologic behavior intermediate between well-differentiated and poorly-differentiated cancers. They are the most commonly seen pattern. Poorly-differentiated or undifferentiated cancers often do not form recognizable glands, are rapidly growing, and can be fatal.

Gleason Grading System: The Gleason Grading System is the most widely used and accepted system for grading prostate cancer. It was devised by Dr. Donald F. Gleason and is based on the architectural patterns of cancer glands observed by the pathologist under the microscope. Dr. Gleason provided a simplified diagram that is used by pathologists throughout the world for assigning grades.

Five Gleason grades are recognized (Grade 1 through 5) – with Grade 1 being the most well-differentiated cancer (slow-growing) and Grade 5 being the most poorly-differentiated cancer (rapidly growing). Gleason grade 1 is rarely, if ever, seen in needle biopsies since the tiny caliber of the biopsy needle does not sample the entire tumor nodule. Grade 1 pattern is generally seen in cancers arising in the transition zone of the prostate.

Click on Variants of Prostate Cancer to see a further examination of the prostate gland and the different types of cancer cells that are found. Prostate cancer displays an amazing variety of patterns. Some of the uncommon variants of prostate cancer are depicted on these pages. Many are high-grade tumors (Gleason grade 4 or 5) while other patterns mimic benign atrophic glands. Also shown is perineural invasion a feature not uncommonly seen in needle biopsies and radical prostatectomy specimens. Perineural invasion may be seen with any variant of prostate cancer. For examples of "conventional" type of prostate cancer, please visit http://www.prostate-help.org/caglegr.htm

The Five Gleason Grades

Grade 1: The least common pattern, especially in needle biopsies. Consists of a circumscribed mass of evenly placed uniform glands that closely resemble normal prostate glands

Grade 2: Cancer glands are similar to those seen in Grade 1 but do not form a circumscribed mass. There may be slight variation in size, shape, and spacing of the glands. The glands can be seen infiltrating (spreading) through the surrounding stroma. Click on Gleason Pattern 2

Grade 3: The most common pattern showing considerable variation in size, shape, and spacing of the glands. Irregular infiltration of the surrounding stroma may impart a ragged appearance to the cancer focus when seen at low-magnification under the microscope.Gleason Pattern 3

Grade 4: The most important feature of this grade is fusion of glands forming an anastomosing network punctuated by glandular lumens. Glands are no longer recognized as individual units.Gleason Pattern 4

Grade 5: The cancer cells form solid sheets and clusters or may infiltrate the prostate as individual cells. Necrosis may be present. There is no attempt at gland formation by cancer.Gleason Pattern 5

To account for the heterogeneity of prostate cancer, the pathologist assigns the primary grade (the most common pattern) and secondary grade (the next most common pattern) to each tumor. Gleason score is obtained by adding the two values. As a rule, the secondary grade should comprise at least 5% of the cancer.

Examples of Gleason Score:

The lowest possible Gleason score is 1+1=2 when both the primary and secondary patterns are Grade 1 - this would be normal and is never used.

The highest possible Gleason score is 5+5=10 when both the primary and secondary patterns are Grade 5

The most commonly observed Gleason score is 3+3=6.

If the biopsies show a tiny focus of cancer with features of Gleason grade 4 and no secondary pattern, the Gleason score would be 4+4=8 (the primary grade is simply doubled).

Should tiny foci of cancer in needle biopsies be graded?

Nowadays, the pathologists are increasingly making diagnosis on tiny foci of cancer in needle biopsies. Due to small tumor volume a secondary pattern may not be observed. In such cases, the primary grade is simply doubled (as shown in the example above). Gleason grading should be applied to all positive biopsies irrespective of the amount of cancer. Studies have shown that overall the correlation of Gleason scores between biopsies and prostatectomy specimens is good. However, it should be understood that the Gleason score of a tiny focus of cancer in a needle biopsy may not be reflective of the overall tumor due to sampling issues. About 30% to 45% of such cases are undergraded when compared to the Gleason grade in the radical prostatectomy specimen.

Is cancer with Gleason score of 3+4=7 different from 4+3=7?

If the biopsies show 60% Gleason grade 3 and the remaining 40% is Gleason grade 4, the Gleason score is 3+4=7. If 60% of the cancer is Gleason grade 4 and 40% is Gleason grade 3, the Gleason score is (4+3=7).

In a study of patients with Gleason score 7 treated by radical prostatectomy, the primary Gleason pattern (4 vs 3) showed a significant correlation with other histologic and clinical predictors of disease progression; however, in a multivariate analysis along with pre-operative PSA, tumor volume, surgical margin status, extraprostatic extension, status of seminal vesicle involvement, and lymph node metastases, the primary Gleason pattern was not an independent predictor of disease progression. (Herman CM et al. Primary Gleason pattern as a predictor of disease progression in Gleason score 7 prostate cancer: a multivariate analysis of 823 men treated with radical prostatectomy. American Journal of Surgical Pathology 2001 May; 25(5):657-60.

What about tertiary Gleason patterns observed in needle biopsies?

When tertiary (third most common) and quaternary (fourth most common) patterns are observed in needle biopsies, they are usually ignored unless they are of higher grade. If three histologic grades are present and 2nd and 3rd grade are roughly equal in proportions, the higher grade is chosen to assign Gleason score. For e.g. if biopsies show 60% Grade 3, 20% Grade 2, and 20% Grade 4, the Gleason score would be 3+4=7.  However the most important part of this diagnosis would be the grade 4 involved.

What about the tertiary Gleason patterns observed in radical prostatectomy specimens?

The Gleason score is derived by adding primary and secondary grades (patterns). It does not take into consideration the tertiary pattern (the third most common pattern). A study has shown that the presence of even small amount tertiary high-grade cancer can have an adverse impact on the outcome. Tumors with Gleason score 7 with a tertiary pattern 5 had significantly worse pathologic stages and higher progression rates than Gleason score 7 tumors without the higher-grade tertiary component (Pan CC et al. The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens: a proposal to modify the Gleason grading system. American Journal of Surgical Pathology 2000 Apr; 24(4):563-9). Studies like this seem to suggest that higher-grade tertiary patterns should be mentioned in the pathology report if present.

For further detail about Gleason Grading and prognostic factors click "here" .

See images of the various Gleason grades of prostate cancer by clicking "here".  See the advanced aggressive variants of prostate cancer by clicking "here" .

For additional information on Gleason from an expert see Dr. Bostwick's very well done paper by clicking "here".

And still more of the Pathology of prostate can be found by clicking "here".