By Gerry J. O’Dowd, Robert W. Veltri,
M. Craig Miller, UroCor, Inc., Oklahoma City, OK;
and Stephen B. Strum, Prostate Cancer Research Institute,
Los Angeles, CA
Reprinted from PCRI Insights January 2001 v4.1
Note: If you have been recently diagnosed with prostate cancer, please see the “NEWLY DIAGNOSED“ section of our website.
Tumor grading of prostate cancer (PC) is a fundamental determinant of disease biology and prognosis. Tumor grading is defined as a property of cancer independent of tumor location found in either biopsy or radical prostatectomy specimens. Prognosis refers to the expected biologic aggressive potential of a patient’s PC to spread to other organs. The Gleason score, the most widespread method of prostate cancer tissue grading used today, is the single most important prognostic factor in PC.1-7 It is one determinant of a patient’s specific risk of dying due to prostate cancer.2,8 Hence, once the diagnosis of prostate cancer is made on biopsy, tumor grading, especially the Gleason score, strongly influences decisions regarding options for therapy.9
The diagnostic quality of prostate biopsies is really a team effort between the urologist and the pathologist (an expert physician trained in the study of disease) working on a patient’s case. A correct prostate cancer diagnosis and Gleason score are possible only when the biopsy is both performed and interpreted correctly by the urologist and pathologist respectively. Incomplete biopsy sampling of the prostate is one reason why the “predicted” Gleason score on biopsy does not always correlate with the actual “observed” Gleason score of the prostate cancer in the gland itself. Hence, the accuracy of Gleason scoring is dependent upon not only on the expertise of the pathologist reading the slides, but also on the completeness and adequacy of the prostate biopsy sampling strategy.10
Currently no clinical standard for transrectal ultrasound biopsy is used by practicing urologists that specifies a particular strategy of systematic sampling of the prostate gland. We know that extending biopsy strategy beyond that of the standard sextant approach will increase the yield of positive biopsies for PC and improve the sensitivity of the transrectal ultrasound technique.11,12 However, given the data from a number of studies showing the unique diagnostic contribution by biopsies from each of 11 separately labeled prostate sites and given commonly observed variations in biopsy quality, we strongly urge urologists to place each biopsy core in an individual container, clearly labeled with the anatomic location or prostate gland site of each biopsy taken.9,13,14,15
Systematic prostate biopsy labeling provides additional clinical information of value in the risk assessment of the patient.16 Anatomic, site specific, biopsy labeling or “prostate biopsy mapping” allows for (1) determination of the total percentage of separate biopsy samples involved by cancer (i.e. often referred to as “the percentage of positive cores”),17-21 (2) the measurement in mm’s of the amount (or the percentage) of linear involvement by PC present in each positive biopsy core at a particular biopsy site,22-25 and (3) the anatomic region or zone of origin (transition zone vs. peripheral zone) of PC involvement.26-33
The Gleason scoring system is based on microscopic tumor patterns assessed by a pathologist while interpreting the biopsy specimen. When PC is present in the biopsy, the Gleason score is based upon the degree of loss of the normal glandular tissue architecture (i.e. shape, size and differentiation of the glands) as originally described and developed by Dr. Donald Gleason in 19741-4. The classic Gleason scoring diagram shows five basic tissue patterns that are technically referred to as tumor “grades”. The subjective microscopic determination of this loss of normal glandular structure caused by the cancer is abstractly represented by a grade, a number ranging from 1 to 5, with 5 being the worst grade possible (See Figure 1). The Gleason score (GS) and the Gleason sum are one and the same. However, the Gleason grade and the Gleason score or sum are different. The biopsy Gleason score is a sum of the primary grade (representing the majority of tumor) and a secondary grade (assigned to the minority of the tumor), and is a number ranging from 2 to 10. The higher the Gleason score, the more aggressive the tumor is likely to act and the worse the patient’s prognosis. Figure 2 provides classical photomicrograph examples of Gleason grade 3, 4, and 5 prostate cancers in needle core biopsy tissue sections.
Here’s how it goes:
The Primary Gleason grade has to be greater than 50% of the total pattern seen (i.e. the pattern of the majority of the cancer observed). The Secondary Gleason grade has to be less than 50%, but at least 5%, of the pattern of the total cancer observed. The sum of the primary and secondary Gleason grades is shown as the Gleason score or sum (i.e. primary grade + secondary grade = GS; i.e. 4+3 or 3+4 = GS 7).
The defects in this scoring system are as follows:
1) Gleason grading and scoring is largely subjective and the range of Gleason scores diagnosed has narrowed to where almost all patients today present with a Gleason score of 6, 7, or 8,34-39 Gleason scores 2-4 should not be made on transrectal prostate biopsies40, and Gleason scores 9 and 10 are uncommon.
2) The medical expert responsible for the grading and scoring (i.e. the pathologists) are not all equally proficient in reading Gleason grades, especially on the small thin needle core tissue samples obtained at biopsy.41,42
3) The Gleason score is not the only key statistic available from the patient’s biopsy, especially in today’s changing pattern of pathologic presentation of PC. GS 7 cancers are a prognostically heterogeneous group of tumors that can be sub-stratified by the amount of Gleason grade 4 or 5 disease present. The proportion of grades 4 and 5 appears to have significant value in the determination of a patient’s prognosis.43-45
4) Analysis of the correctness of this important diagnostic call has been made by correlating the predicted Gleason score of the biopsy with that observed in the radical prostatectomy surgical specimen. Unfortunately errors in the predicted biopsy Gleason score are common and most often result in under-grading (by greater than or equal to 1.0 grade level) of the actual tumor.7,35,46-48
The above limitations of GS indicate the clinical need to avoid under-grading GS 6 and to substratify GS 7 tumors in some clinically useful way. Under-grading of the predicted Gleason scores of prostate cancers on biopsy under estimates the potential risk of disease progression and may significantly impact the success or failure of the chosen primary treatment modality (surgery, radiation therapy, cryosurgery, or watchful waiting). Undergrading will especially affect the success of “ watchful waiting”, and the observed efficacy of some of the newer treatment modalities like brachytherapy, and it also will conceal the need for adjuvant therapy in high risk patients who need it the most.
As the title of this article indicates, the Gleason score is not the only key prognostic factor available from your biopsy, especially in today’s changing pattern of pathologic presentation for PC. As previously noted, the Gleason score can be anywhere from 2-10, since the Gleason grades range from 1-5 for the primary grade and 1-5 for the secondary grade. Table 1 illustrates the distribution of Gleason score readings for 54,200 patients with PC that were processed and diagnosed between 3/94 and 9/98 by a single central expert reference laboratory. This table also demonstrates the correlation between Gleason scoring and the patient’s age, the number of positive cores, and the total percent of linear tumor involvement.34
Table 1 shows the analysis of 54,200 prostate biopsies containing prostate cancer from over 151,000 prostate biopsy cases collected over a four year period. The majority of men present with either GS 6 (48%) or GS 7 (33%) prostate cancer. There are a relatively small number (2%) of men with low Gleason score (GS) cancers (i.e. GS 2 – 5). This table also shows that as you get older, you are more likely to have a more aggressive cancer (i.e. higher GS, more positive cores, and a greater volume of tumor). The “Total % Involvement” column is the sum of the % involvement of all positive cores, and can be a number anywhere from 0.5% up to 1,200% (if you have 12 positive cores with 100% involvement) and beyond. This number can be viewed as an indicator of tumor volume. Lastly, this table shows that as the GS increases, the volume of the tumor also increases (i.e. increasing number of positive cores and % tumor involvement).
We know through the excellent work of McNeal and Stamey that the amount of Gleason grades 4 and 5 relate to the overall prognosis of the patient.43-45 This is not a final verdict, but is usually a strong and important factor regarding the outcome of the patient. A quantitative interpretation of today’s biopsies should also include the percentage of positive biopsy samples, the zonal origin of the biopsy specimen with cancer if possible (transition zone vs. peripheral zone), the notation of the presence or absence of invasion of the pericapsular fat49 (fatty tissue around the capsule of the prostate) and the perineural invasion50-53 (invasion of nerve radicles) by the cancer. It should also include the quantitative amount of cancer present on each positive tissue core presented in the biopsy. The latter information has been shown to be related to the PC’s aggressive nature as well as the relative tumor size, both of which have prognostic value.10,16,19,20,22-24,30,32,35,50,54
Some alternatives to the classic Gleason scoring system have been proposed. One involves the conversion of the Gleason grading system to one that is more objective and quantitative using new methods of image analysis that would mathematically convert the Gleason grade to a continuous quantitative variable. This type of effort has been published but remains in the research and development stage.55-58
Another approach would be to use supplemental testing to sub-stratify Gleason score 6 and 7 cases. One example of this approach would be the use of DNA ploidy image analysis to identify abnormal DNA ploidy cases.59-60 DNA ploidy uses expert-selected cancer cell nuclei from a PC biopsy specimen to determine the amount of DNA present in the cells. The cells are stained with a Feulgen stain that binds to the DNA of the cell in a way that permits direct quantitation of the DNA using a special microscope interfaced with a computer, a digital camera, and a software program to analyze the DNA content of the nuclear images. However, a study by Carmichael et al indicated that ploidy analysis on tissue sections was more predictive of recurrence post-radical prostatectomy than ploidy done on individual cell nuclei.59 A poor prognostic DNA ploidy result is represented as aneuploid or tetraploid, whereas a good prognostic result is interpreted as diploid. These interpretations actually refer to the relative numbers of chromosomes (amount of DNA) present in the cells (usually about 125- 150 cells) that were analyzed. A normal amount of chromosomes would be 22 pairs (maternal and paternal sets) plus a pair of sex chromosomes, for a total of 46.
Table 2 illustrates the relationship between DNA ploidy results and Gleason scores for 35,391 prostate cancer biopsies analyzed from 3/94 to 9/98. Please note that even cases of Gleason score 6 have a large group that have abnormal DNA ploidy (38%), which would suggest a poorer prognosis than the tumor grade would imply. Also, note the direct correlation between increasing Gleason score and the percentage of cases with abnormal DNA ploidy. Gleason Grade 4/5, the amount of tumor involvement, the perineural invasion status in the biopsy, and DNA ploidy allow for a more comprehensive patient disease profile to guide treatment decisions. In other words, it is a significant contribution to the risk assessment of the patient.
Table 2 shows a comparison of the DNA ploidy analysis result and the Gleason scores in 35,931 prostate biopsies collected over a four year period. The majority of low GS tumors (i.e. GS 2-5) have a normal DNA ploidy, which indicates a less aggressive tumor and a good prognosis. Conversely, most of the high GS tumors (i.e. 8 – 10) have an abnormal DNA ploidy (i.e. aneuploid and/or tetraploid), indicating an aggressive tumor and a poor prognosis. This table also shows that approximately 1/3 of the GS 6 tumors have an abnormal DNA ploidy and are probably more aggressive than they appear, and that the same amount of GS 7 tumors have a normal DNA ploidy and possibly have a fairly decent prognosis.
Finally, based in part on the tumor volume and grading measurements of radical prostatectomy specimens by Stamey et al,43 Dr. Stephen Strum has proposed to pathologists like Dr. David Bostwick and urologists such as Dr. Alan Partin the use of Gleason Differential (GD). The GD would give us the breakdown of the relative proportions or amounts of primary and secondary GG. This is how it would look: Patient “A” has a GS of 7 that is a (4+3). This means that the GG 4 can range anywhere from 51% to 95%. A better expression of information would be to show the patient’s GS and GD as (4+3)[%GG 4/ %GG 3]. If patient “A” had 70% GG4 and 30% GG3, this would be shown as (4,3)[70/30].
The prognostic value of estimating or measuring the quantity of Gleason Grade 4 and 5, however, has been demonstrated only in RP specimens and has not been proven in biopsies as of this time. Studies need to be conducted to assess the prognostic value of quantitative Grade 4 and 5 measurements in biopsy specimens for patient outcomes. Notwithstanding the lack of patient outcomes data based on biopsy grading results, there is growing support for this biopsy grading concept. Stamey has proposed that the Gleason sum be followed by the % Grade 4 and/or 5. These figures should be used in evaluating the role of the GS with the breakdown of the GD.
Gleason Score or GS =
Gleason Grade or GG =
Gleason Differential or GD =
Additional Data On Value Of Gleason 3/4 Grading:
In the November issue of Urology, Sakr et al38 reported findings on 534 patients with GS 7 at RP. Patients with GS 4+3 had more advanced clinical and pathological stages, larger tumor volumes, higher preoperative PSA levels, older age and a higher proportion were African-American men compared to GS 3+4 patients. Differences in tumor volumes are shown in Table 3.
Table adapted from Sakr et al 38
In the same issue of Urology, Chan et al39 presented an assessment of the prognostic value of Gleason score (3+4) versus (4+3) at RP. The findings are summarized in Table 4.
Table adapted from the paper by Chan et al 39
Clearly, relative proportion of high Gleason grades in a given tumor is more critical than the Gleason score by itself, especially as noted in studies of radical prostatectomy cases for which long-term follow-up is available. However, the published literature has confirmed the value of accurate Gleason grading on thin needle biopsies as well as the added value of capturing and reporting information such as the percentage of positive biopsy specimens, the amount of Gleason grade 4/5 tumor, presence of perineural invasion, pericapsular fat invasion, and abnormal ploidy within the subset of Gleason score 6 or 7 biopsies.10,18-20,43,49,59
Our Words of Advice on the GS
In summary, an accurate prognosis is not just a Gleason score — it is a complete and thorough interpretation of all the pathological and clinical information available from the prostate biopsy material! Throughout our counseling of men with PC, we continue to strongly advise that the Gleason score be read by either an experienced uropathologist of acclaimed expertise or a laboratory known for its focus on urology and having a high level of accuracy in its pathologic interpretation of prostate biopsies. In this regard, Dr. Strum has appended the following message to thousands of email postings and consultations and continues to apply it as a basic principle in the management of PC.
“Because the Gleason score is such a critical piece of information, I would want to have an expert pathology opinion. This should be obtained from a prostate cancer pathology expert. The ones that I am most familiar with include:
List omitted – a list of suggested Pathologists can be obtained by emailing firstname.lastname@example.org
A second opinion on the pathology is usually covered by insurance but if not, runs about $150. A copy of the original pathology report with the actual slides or recuts from the tissue paraffin block is sent to the outside reviewer. A copy of the insurance information is usually sent along with this. Either you or your primary care doctor or specialist can initiate such a second opinion.”
Editor’s Note: Since the posting of this message the costs of second opinions on pathology specimens has increased. The Medicare allowable for such a service is now $300. In addition, a few changes have been made to the list of PC pathology experts.
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