Monday, June 17, 2013
A review by Ralph Valle
In 1974, Dr. Donald F. Gleason, a noted pathologist, created a prostate cancer grading system derived from a study that included 2,900 patients. The objective was to provide a more accurate way for pathologists to grade prostate cancer. This system is widely accepted and used universally. The Gleason system is based exclusively on the architectural pattern of the glands of the prostate tumor. A normal prostate has glands made up by cells that have differentiated and assembled in a particular architectural structure. As cancer cells proliferate and form tumors, a process of dedifferentiation disrupts the glandular architectural pattern.
A tumor whose structure is nearly normal (well differentiated) has a biological behavior relatively close to normal and is not very aggressively malignant. At the other extreme, a tumor whose structure has regressed to a more primitive form (poorly differentiated) is aggressively malignant. Those are the two extremes of the Gleason grading system identifying the progressive deterioration of the cancer cell architecture.
Prostate cancer is the most diagnosed cancer in males and the second cause of cancer mortality. It is a serious disease in the world of men’s health. At the present time, the most reliable way to evaluate a patient’s prognosis is to obtain the most expert opinion on the biopsy core samples. Why is this of utmost importance? Critical treatment decisions are made based on this grading. The significance of the Gleason grading system is on predicting how aggressive is the evaluated sample. This is done by direct expert observation of the tissue samples under a low power microscope. The experience of the pathologist doing the grading is of extreme importance.
It is evident that in most multi-cellular organisms, such as humans, not all cells are alike. As an example, cells that make up the human skin are different from cells that make up organs or glands. And yet, all of the different cell types in the human body are derived from a single, fertilized egg cell through a process of differentiation. Differentiation is the process by which an unspecialized (undifferentiated) cell becomes specialized into one of the many cells that make up the body, such as brain, lung, or prostate cells. During differentiation, certain genes are turned on, or activated, while other genes are switched off, or inactivated. This process is highly regulated. As a result, a differentiated cell will develop specific architectural glandular structures and perform certain characteristic functions. When specialized cells such as prostate cells, undergo genetic mutations, they can in time dedifferentiate and lose their specific architectural structures and characteristics. This is the basis for the Gleason Grading System.
The Gleason Grades*
Dr. Gleason proposed five progressive steps in the process of dedifferentiation to identify the patient’s degree of disease aggressiveness.
Grades I and II:
These grades depict the initial changes in the formation of prostate cancer. The glandular architecture resembles normal patterns. Because of their close appearance to normal, these grades are classified as well differentiated. Gleason grade I tumors consist of closely packed, uniform, round glands arranged in a nodule with pushing borders. This pattern is very uncommon except in transition zone adenocarcinomas and is almost never seen in needle biopsy specimens. Gleason grade II tumors are similar to grade I tumors, except the glands show more variability in size and shape.
This is the most common grade found at evaluation and is considered moderately well differentiated (slightly more dedifferentiated than grades I and II). In Grade III like with Grades I and II, the gland unit formation is still preserved although more invading glands are prominent and become a defining feature of this grade. Growth between benign glands is a useful clue to this grade.
This is a critical grade since, if detected, the patient’s prognosis is usually poorer by a considerable degree. There is a notable loss of glandular architecture and disruption and loss of the normal gland unit. Grade IV is identified almost entirely by loss of the ability to form individual, separate gland units, each with its separate secretory space (Lumen). This important distinction is simple in concept but complex in practice. The reason is that there are a variety of different-appearing ways in which the cancer's effort to form gland units can be distorted. Much experience is required for this diagnosis, and not all patterns are easily distinguishable from grade III. This is the main class of poorly differentiated prostate cancer, and its distinction from grade III is the most commonly important grading decision.
This is the last step in the multi-step of dedifferentiation. This grade conveys a poor prognosis. Its overall importance for the general population is reduced by the fact that it is less common than grade IV, and it is seldom seen in men whose prostate cancer is diagnosed early in its development. This grade also shows a variety of patterns, all of which demonstrate no evidence of any attempt to form gland units. This grade is often called undifferentiated, because its features are so primitive that it is not easily distinguished from other undifferentiated cancers originating in other organs.
Prostate cancer is notably heter-ogeneous. One tumor can contain different grades. As the system was being developed, Dr. Gleason noticed that, by combining the two most prevalent patterns in a tissue sample, he could better predict the patient’s prognosis. The Gleason Score is therefore the sum of the most prevalent grade and the second most prevalent grade present in the tissue sample.Since there are five grades, then mathematically nine different scores are possible with 25 different number combinations. Although possible, many of these combinations are seldom seen in actual practice. Since the advent of PSA testing, the most common scores are GS 6 (3 + 3) and GS 7 (3 + 4), (4 + 3)
Well Differentiated ------- Gleason Scores: 2, 3, 4 and 5
GS (1 + 1), (1 + 2), (2 + 1), (1 + 3), (3 + 1), (2 + 2), (2 + 3), (3 + 2), (1 + 4), (4 + 1)
Moderately Well Differentiated ---------- Gleason Score: 6
GS (3 + 3), (2 + 4), (4 + 2), (1 + 5), (5 + 1)
Moderately Poorly Differentiated to Poorly Differentiated ------ GS 7, 8, 9 and 10
GS (3 + 4), (4 + 3), (2 + 5), (5 + 2), (3 + 5), (5 + 3), (4 + 4), (4 + 5), (5 + 4), (5 + 5)
What is the significance of the Gleason Score?
The grade of a prostate cancer specimen is very valuable to doctors in helping them to understand how a particular case of prostate cancer can be treated. In general, the time for which a patient is likely to survive following a diagnosis of prostate cancer is related to the Gleason score. The lower the Gleason score, the better the patient is likely to do. The Gleason Score is a measurement of how aggressive the cancer can potentially be and significantly impacts treatment decisions. It is important to understand that the score represents the evaluation of the tissue samples obtained from the prostate gland and although there is a significant correlation it is not necessarily a total representation of the tumor load in the gland. The multifocal character of prostate cancer has been well established. Thus, to minimize the potential of missing the presence of aggressive cancer foci, the number of biopsy sample cores has been increased to better map the gland in order to obtain a closer representation of the tumor load. This plus expert evaluation provides the patient with a better tool to make a treatment/no treatment decision. Still, it should be understood that the score provided represents the score of the biopsy sample provided and not of the whole prostate gland. It has been noted that there is a significant tendency to undergrade scores.
Prostate cancer is a multi-step progressive disease with a wide-range, variable time span. In most men the disease progresses slowly, but in others progression is fast and unrelenting. In either case, the common factor is that disease progression is a continuum and, given enough time, it evolves into a lethal disease by the process of dedifferentiation. In his histological observation of tumors, Dr. Gleason recognized the multi-step process that characterizes the heterogeneity of prostate tumors and was able to more closely characterize a patient’s prognosis by grading the two most prevalent patterns present in a tissue sample.
Dr. B. Tribukait and coworkers in Sweden have supported the multi-step progression of prostate cancer with their work on successive needle aspirations of prostate tumors. They evaluated the yearly rate of mutation accumulation as determined by DNA ploidy measurements. In each cell of their bodies, except their germ cells, humans have 23 pairs of chromosomes that dictate the person’s genetic makeup. Normal cells containing 23 pairs of chromosomes are said to be diploid. Dr. Tribukait was able to show that, as time goes by and mutations accumulate, there is a loss or gain of chromosomes in prostate tumors. This process changes the cells from diploid to aneuploid. Aneuploid cells are cells containing an abnormal number of chromosomes. There is a close relationship between DNA ploidy and Gleason Grades. Higher Gleason Grades are mostly aneuploid and tend to metastasize or invade local tissues more readily.
In his March 15, 2005 lecture at the Prostate Cancer Information and Support Group of the Mid-Hudson Valley, New York State, Dr. Howard Scher commented on this gradual process in which well-differentiated tumors become more aggressive in time and evolve into higher-grade cancers with the potential to become metastatic and invade distant tissues. Further support for this process exists from autopsy results of younger men dying an accidental death. Although the presence of prostate cancer is apparent at even the third decade of life, all those cancers are classified as insignificant and always well differentiated. The implication is that, if those cancers had more time to progress, more aggressive tumors would have developed in time (higher Gleason grades) —which is what typically happens when men are diagnosed at a later point in their lifespan.
In summary, the importance of a proper Gleason Grade evaluation is THE most important diagnostic tool prostate cancer patients presently have. The treating physicians and newly diagnosed patients do not always recognize this fact. It is up to the patient to request a second opinion by an expert in prostate pathology who should examine the tissue samples and render an opinion. Because of its ultimate significance in the treatment decision-making process, this is an important fact to disseminate in support groups and today’s prostate cancer advocacy movement, because of its ultimate significance in the decision-making process for treatment and treatment outcomes. .
A microarray is a tool presently in use by researchers to analyze gene expression. It consists of a small membrane or glass slide containing samples of a great number of genes arranged in a regular pattern. When exposed to genetic material it tells which genes are switched on and which are off. This technique had been made possible by the completion of the Human Genome Project and the development of a very advanced tissue dissection (sampling) technique known as laser capture microdissection and the availability of technologies such as unbiased RNA amplification.
In place of a subjective Gleason Grade observation of a tissue sample, in time pathologists will be able to create a molecular profile that more closely correlates with the true nature of the disease. It will identify disease that requires treatment and disease that does not. This will be a major step in the identification of patients that will benefit from treatment, as well as those that do not. The science is not commercially available as yet, but it will certainly be a great benefit to patients in the not too distant future.
*The Prostate Cancer InfoLink originally developed part of the text used for the Gleason Grade description. It is reproduced here with the permission of Vox Medica. Visit: http://www.phoenix5.org/Infolink/
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