Gleason 7: A New Risk Category?
A man is told he has prostate cancer. Besides the basic PSA blood test, the DRE (digital rectal exam) and a biopsy, what other tests can be used to help determine the type and extent of his particular cancer? Can tests tell him what kind of treatment he should get? How accurate are those tests? Where can he get them? These are some of the basic questions we've all asked when faced with this frightening diagnosis.
In fact, new and better diagnostic tools are the focus of much research and development. The goal is to more accurately predict whether the cancer is aggressive or not and, therefore, to select the most appropriate treatment regimen. One of these tools is the Gleason Score. A Gleason Score is determined from the analysis of tissue samples taken from the prostate during the biopsy. The samples are assigned a grade of 1 through 5: Grade 1 samples most resemble the normal prostate; Grade 5 has the potential for aggressive growth. The final Gleason Score is the sum of two such samples.
In this article, we will be speaking with Dr. Ronald Morton (Director of Laboratories, The Baylor Prostate Center and Assistant Professor, Department of Cell Biology, Scott Department of Urology, Baylor College of Medicine; Chief of Urology at the Houston Veterans Administration Medical Center). Dr. Morton's current research is focused on patients who have been given a diagnosis of Gleason 7. His studies indicate the critical need for a unique treatment approach for these patients.
DC: Dr. Morton, can you give us a brief definition of Gleason Grade?
RM: The Gleason grading system is based on the glandular pattern of the tumor. Gleason grade takes into account the ability of the tumor to form glands. A pathologist, using relatively low magnification, performs the histologic review necessary for assigning the Gleason grade. The range of grades is 1-5: 1, 2 & 3 are considered to be low to moderate in grade; 4 & 5 are considered to be high grade. When developing his grading system, Gleason noted that the prognosis for a given patient fell somewhere between that predicted by the primary grade and a secondary grade given to the second most prominent glandular pattern. When the two grades were summed, the total Gleason Score was a more accurate predictor of outcome than either of the individual grades. Thus the traditionally reported Gleason score will be the sum of two numbers between 1-5 with a total score from 2-10. The individual cellular features of anaplasia, that would be seen on high-powered views, do not provide additional prognostic information but are generally noted if they are significant.
DC: Why should we have a Gleason score before we select a treatment option?
RM: When considering a grading system for prostate cancer or any other cancer there are several important aspects to consider. Two of the most critical features are: 1) the reproducibility of the grading system and, 2) the prognostic ability of the grading system. The Gleason grading system is quite reproducible among board certified pathologists. What I mean by that is when comparing pathologists’ ability to assign Gleason grade, there is generally 90% agreement (within 1 grade) on the Gleason sum scale. Therefore, patients can feel comfortable that the Gleason sum reported by a reputable pathologist is an accurate representation of the grade of their disease.
Perhaps of greater importance, there is a strong correlation between Gleason sum and treatment outcome, both for radical prostatectomy as well as radiation therapy. All of the instruments used to predict disease free survival such as nomograms that have been published by Partin, Naryan, and Kattan, incorporate Gleason grade into the prediction model. So the Gleason grade is reliable and provides invaluable information for both the patient and urologist as they consider the many treatment options available for prostate cancer.
DC: What does research show about the significance of Gleason Grade 7 versus a grade of 6 or lower?
RM: Remember that Gleason grade 1-3 is considered well to moderately well differentiated. Accordingly, Gleason sum 6 or less tumors can be considered to be moderately to well-differentiated Since it is unusual for the primary and secondary Gleason grade to differ by more than one, the only way that there can be a Gleason sum 7 tumor is if the primary or secondary Gleason grade is 4. Because of the Gleason 4 part of the equation, these tumors can behave in a much more aggressive fashion than Gleason sum 6 cancers.
In a study of over 300 patients in Sweden, the disease specific survival for Gleason 7 patients was 10 years. In contrast, Gleason 6 patients survived 16 years and Gleason 4-5 for 20 years. We and many other groups have investigated this question and it is clear that the prognosis for men with Gleason score 7 tumors is worse than for men with Gleason 5 & 6 tumors. In fact, under certain circumstances it is suggested that men with Gleason 7 tumors can be considered for clinical trials.
DC: Given a Gleason Score of 7, is there a difference between 3 + 4 and 4 + 3?
RM: While we are certain that Gleason score 7 tumors behave in a more aggressive fashion than do Gleason 5 and 6 tumors, it is less clear whether or not it makes a difference if the primary or secondary pattern accounts for the Gleason 4 grade. Some studies have shown Gleason 4+3 to be a worse prognostic sign than is Gleason 3+4. However, this has not always been the case and there are studies that find no difference between the two scores. There has not been a prospective study that has attempted to answer this question and it remains a controversial point.
I think that a patient needs to understand that he is at increased risk for both advanced pathologic grade as well as tumor recurrence if he has any component of Gleason 4 in his pretreatment biopsy. He should also understand that he must be certain to follow-up with his physician on a regular basis and have frequent PSA tests. It is clear that adjuvant therapies have the best chance to work when given at the earliest signs of disease progression.
DC: With a Gleason 7 is it likely that some cancer cells may already have escaped the prostatic capsule?
RM: Gleason sum 7 tumors are more likely to have worse pathologic stage than Gleason 5 or 6 tumors. The mean tumor volume for Gleason 7 tumors is 5.1 cc’s compared to ~2.5 cc's for Gleason 5 and 6 tumors. The positive margin rates are 20% for Gleason 5, 29% for Gleason 6, and 48% for Gleason 7. Likewise, there is about a 10-fold increase in the risk of positive lymph nodes and/or seminal vesicles when Gleason 7 is compared to Gleason 5 & 6.
DC: Can other tests, such as the RT-PCR blood test or the endo-rectal MRI help us predict the extent of the disease; are they more accurate and widely available?
RM: Although these tests showed initial promise they have not stood the test of time. Neither RT-PCR data nor MRI data have been shown to add to currently available clinical data in multivariable analyses. While I believe that each merits continued research, I don't think that patients should seek out these tests when making a treatment decision. We do offer the RT-PCR test, but for research purposes only.
DC: What can we do if our urologist only uses the basic diagnostic tests (PSA--free vs. bound, CAT scan, bone scan)? How can we get access to other tests or find a specialist?
RM: The indications for tests other than those performed in standard clinical practice have not been substantiated for prostate cancer. We are now offering PET scanning under certain high-risk circumstances; however, using an evidence based medicine approach, the information obtained on a PET scan does not yet increase our ability to predict a given patient's clinical outcome. Whether or not this develops into an important clinical tool can only be answered by well designed clinical studies.
DC: How can we attack any prostate cancer cells that are already outside of the prostate?
RM: This is perhaps one of the most disappointing areas of medical oncology. We have excellent treatment options for clinically and pathologically confined prostate cancer. However, we have not been very successful at developing systemic therapies for this disease. There are novel chemotherapeutic regimens being tested. Notably, the use of Thalidomide as an angiogenesis inhibitor has shown significant activity in prostate cancer. In addition to chemotherapy there are several gene therapy programs aimed at metastatic prostate cancer. To date we do not have a proven therapy for metastatic prostate cancer. I think that it is important for patients to understand that in order to develop such therapies we need to enroll patients into clinical trials. If their physician is not familiar with candidate clinical trials, they should seek out this information themselves. Perhaps the best web site to find information is the National Cancer Institute web page.
(DC note: The Centerwatch web site is another resource. You can register for e-mail notification about trials specific to prostate cancer.)
DC: Please describe your vision of a team approach to diagnosis and treatment for a newly diagnosed prostate cancer patient.
RM: I think that there is growing enthusiasm for a multidisciplinary approach to prostate cancer. That is, the medical oncologist, radiation oncologist, and urologist cooperate in planning the treatment plan for each patient. This has the advantage of making sure that the patient is fully familiar with each of his treatment options. An added benefit is that high risk patients, such as Gleason 7 patients, can be identified and engage in early discussions of what their options are if they have locally advanced disease or suffer a recurrence after completion of their primary treatment.
DC: What can we do to make that happen if we aren't being treated at a major medical center like Baylor?
RM: Major centers like Baylor, Johns Hopkins, University of Michigan, and M.D. Anderson and a handful of others offer well coordinated comprehensive prostate cancer treatment programs. Patients should seek out centers such as these if they feel they may be in a high risk category.
DC Note: the National Comprehensive Cancer Network lists many centers of excellence; however, you should also look for the NCI-designated Cancer Centers as well as centers affiliated with major university medical centers.
DC: Thank you, Dr. Morton, for sharing this crucial information with us. To reiterate some of your main points, you recommend that men with a Gleason Score of 7 seek treatment as early as possible, consider therapies beyond surgery and radiation, and have frequent follow-ups, preferably with a team of specialists they've assembled. We are grateful for your hard work and for taking the time to explain your research and findings to us.
- Diane Johnson
For more information on clinical trials, what they are and how they work, and what drugs the NCI is currently evaluating, click HERE
And, for more information on the research process, as well as details relating to advanced stage prostate cancer, see our Research Review page