A survivor’s view

Ralph Valle

Prostate cancer has a natural history. It was written long before the advent of the PSA era, and the best documented details of that history exist in the Scandinavian countries cancer registries and prostate cancer studies that depict what happens when prostate cancer goes untreated.
For the most part, between 1970 and 1990 prostate cancer in that part of Europe was treated conservatively. This treatment consisted in the palliation of symptoms if they existed. Otherwise, if a man was asymptomatic nothing was done. By looking at what happened with untreated prostate cancer we could learn how the disease behaves undisturbed.

There is need to clarify that the existing data is a bit corrupt because as mentioned before, if a man was symptomatic he might have been hormonally suppressed with an orchiectomy or treated with estrogen to abate symptoms and STILL reported as on conservative treatment. As we know, depending on the stage of the disease, hormone suppression can alter the natural progression of prostate cancer and potentially increase survival. This complicates the situation when the data is mixed, but it still gives an indication of how prostate cancer behaves in such setting; that is untreated or treated with hormone suppression in a delayed form and no definitive localized treatment.

What has happened when prostate cancer goes untreated? There are several studies with several conclusions:
1. Johansson JE et al did a population-based study at Orebro, Sweden. A group of 642 patients with prostate cancer of any stage, consecutively diagnosed between 1977 and 1984 at a mean age of 72 years with complete follow-up to 1994. RESULTS: In the entire cohort, prostate cancer accounted for 201 (37%) of all 541 deaths. Among 300 patients with a diagnosis of localized disease (T0-T2), 33 (11%) died of prostate cancer. In this group, the corrected 15-year survival rate was similar in 223 patients with deferred treatment (81%; 95% CI, 72%-89%) and in 77 who received initial treatment (81%; 95% CI, 67%-95%). The corrected 15-year survival was 57% (95% CI, 45%-68%) in 183 patients with locally advanced cancer (T3-T4) and 6% (95% CI, 0%-12%) in those 159 who had distant metastases at the time of diagnosis. CONCLUSION: Patients with localized prostate cancer have a favorable outlook following watchful waiting, and the number of deaths potentially avoidable by radical initial treatment is limited. Without reliable prognostic indicators, an aggressive approach to all patients with early disease would entail substantial overtreatment. In contrast, patients with locally advanced or metastatic disease need trials of aggressive therapy to improve their poor prognosis.

2. Gronberg H et al did a similar study, but the study population was composed of 6514 patients diagnosed with prostate cancer during 1971 to 1987 in northern Sweden. For those who died during follow-up, the cause of death was determined from the comprehensive Swedish registry data (population registries and causes of death registry). RESULTS: About 85% of these patients died during the 7 to 23 years of follow-up, and the prostate cancer-specific mortality was estimated to be 55%. Age at diagnosis was found to be a strong predictor of prostate cancer death. Patients diagnosed before the age of 60 had an 80% risk of dying of prostate cancer, whereas those over 80 years of age at diagnosis had less than a 50% risk of prostate cancer-related death. CONCLUSIONS: The prostate cancer mortality is high but decreases with older age at diagnosis. We found, using data from the causes of death registry, that the relative survival and the cause-specific survival of these patients were compatible with each other.

3. Gronberg H et al. Patient age per se can be a significant prognostic factor in prostate cancer. To investigate this issue age-specific relative survival was analyzed, and the number of years lost due to this disease was calculated in a large and unselected cohort of 6,890 prostate cancer patients diagnosed between 1971 and 1987 in the northern region of Sweden. The tumor grade was derived from filed notification forms, which showed 26.4% well (grade 1), 40.0% moderately (grade 2) and 17.7% poorly (grade 3) differentiated tumors. There was an overrepresentation of grade 3 tumors among the youngest patients. The age-specific relative survival rate did not differ significantly among different age groups and slight differences almost vanished when adjusting for tumor grade. This finding does not support the view that tumors appearing in younger patients are more aggressive per se. However, loss of life expectancy differed significantly among all age classes and in all 3 grades. In patients with grade 1 tumors the years lost due to prostate cancer ranged from 11.0 to 1.2 in the youngest and oldest age strata, even though the relative survival was approximately 0.70 in all age classes. It was concluded that even if relative survival is constant with patient age, the absolute impact of prostate cancer at different ages varied substantially as indicated by loss of life expectancy. This finding might indicate that younger prostate cancer patients should be given more aggressive treatment than older patients.

4. Adolfsson J et al., PURPOSE: We prospectively investigated long-term survival in select men with locally advanced, nonmetastatic prostate cancer managed with deferred treatment. MATERIALS AND METHODS: A total of 50 patients with prostate cancer clinically outside the prostatic capsule and without distant metastases were included in a surveillance protocol. The men were treated if and when symptoms occurred or upon request. The series was followed until December 1994. No patient was lost to followup. RESULTS: Median patient age at diagnosis was 71 years. All patients were followed more than 144 months or died before then. Actual (cumulative incidence) overall and disease specific survival rates at 5, 10 and 12 years were 68 and 90, 34 and 74, and 26 and 70%, respectively. A third of the patients had not received antitumor treatment at followup or before death. CONCLUSIONS: When managed with deferred treatment non-poorly differentiated, locally advanced nonmetastatic prostate cancer seems to have a poorer survival outcome than similarly managed clinically localized prostate cancer. However, compared with other treatments and in terms of survival deferred treatment may be an option for select patients with such tumors and a life expectancy of 10 years or less.

5. Adolfsson J From 1978 to 1982, 172 patients with T1-3, Nx, M0 prostate cancer were included in a surveillance protocol with deferred treatment on symptomatic progression. The median age at diagnosis was 68 (38-89) years. The disease-specific survival at 10 years was 80% for the total series, 84% for the subgroup with T1-2 tumors, and 92% for patients with T1-2 tumors diagnosed when the patients were less than 70 years old . For the subgroup with T3 tumors, the disease-specific survival at 9 years was 70%. In all subgroups the competing mortality was higher than the prostate cancer mortality. Deferred treatment appears to be an acceptable treatment option for patients with a tumor clinically confined to the prostate with a life expectancy of 10 years or less.

As you can see, there is great variability of results, but one thing seems to be obvious. Early disease can be treated successfully with conservative therapy in older men with at least 10 years of life expectancy. More aggressive prostate cancer results in a high rate of mortality when left untreated. Age is an important factor in decision-making. If early disease is diagnosed at a young age there is a high risk of dying from prostate cancer if treated conservatively. The bottom line is that men need to evaluate their disease and understand the uncertainties of the present diagnostic methods before they jump into any treatment or decide to do just plain observation.

Outside of the Scandinavian studies, Albertsen P et al.here in the U.S.A., have  published a study about the risks of surviving prostate cancer. "Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer." CONTEXT: The appropriate therapy for men with localized prostate cancer is uncertain. Until results of clinical trials are available, men and their physicians need guidance. OBJECTIVE: To estimate survival based on a competing risk analysis stratified by age at diagnosis and histologic findings for men diagnosed as having clinically localized prostate cancer and who were managed conservatively. DESIGN: Retrospective cohort study. SETTING: Connecticut Tumor Registry. PATIENTS: A total of 767 men with localized prostate cancer diagnosed between 1971 and 1984, aged 55 to 74 years at diagnosis, either not treated or treated with immediate or delayed hormonal therapy, and followed up for 10 to 20 years after diagnosis. MAIN OUTCOME MEASURES: Estimates of the probability of dying from prostate cancer or other competing hazards. RESULTS: Men with tumors that have Gleason scores of 2 to 4, 5, 6, 7, and 8 to 10 face a 4% to 7%, 6% to 11%, 18% to 30%, 42% to 70%, and 60% to 87% chance, respectively, of dying from prostate cancer within 15 years of diagnosis depending on their age at diagnosis. CONCLUSIONS: Men whose prostate biopsy specimens show Gleason score 2 to 4 disease face a minimal risk of death from prostate cancer within 15 years of diagnosis. Conversely, men whose biopsy specimens show Gleason score 7 to 10 disease face a high risk of death from prostate cancer when treated conservatively, even when cancer is diagnosed as late as age 74 years. Men with Gleason score 5 or 6 tumors face a modest risk of death from prostate cancer that increases slowly over at least 15 years of follow-up.

I wrote an e-mail query to Dr. Albertsen about this study, asking for guidance on what to tell a 55-year-old man diagnosed with PCa with respect to conservative management because I meet some of those in my support groups. Here is what he answered (I also requested authorization to publish his response):
“Concerning your 55 year old man, I would recommend the following. If he has high-grade disease, our study indicates that he has a high probability of dying from prostate cancer if he elects conservative treatment. Therefore I would encourage him to do something. For men with low-grade disease, this is a difficult problem. I would probably still recommend more aggressive treatment because of the long life expectancy, but if the patient wanted to wait because of potency concerns or something else, our study tries to estimate his probability of progression over a period of 15 years.”

In numerous conversations with those supportive of conservative treatment, the side effects of treatment affecting QOL are almost always mentioned. The fact that treatment and conservative treatment yield similar survival figures at 10 years is standard in such conversations. They tell me, if you avoid treatment side effects and at the same time live the same number of years as those undergoing damaging treatments, why would anyone with a sane mind undergo treatment?

The assumption that prostate cancer progression happens without inflicting any symptoms affecting QOL is totally ignored in the above matrix. It never ceases to amaze me that such assumption is invariably taken for granted. Prostate cancer progression can cause impotence, incontinence, urinary blockage, kidney failure, bone metastasis, compression fractures and major organ metastatic involvement causing major symptoms and eventually death.

The fact that diet seems to be involved in the development of clinical stages of prostate cancer is of great preventive potential. Could the proper diet slowdown disease progression once diagnosed? Several studies seem to support that fact although it is not known if the effect would apply to all stages of the disease.

Going back to our historic recount, while those Scandinavian countries were exclusively applying conservative management to prostate cancer, a more aggressive school of medicine developed here. Surgery and radiation treatments came about as a result of this aggressive thought process. In looking at the original attempts to improve survival with these aggressive methods, one has to conclude that because of an ever-increasing mortality rate, nothing much was accomplished. The mortality rate climbed steadily during this period. What is worse, studies demonstrated that the side effects of these treatments were considerable. The medical profession,  in its quest to promote survival in a few individuals that might have benefited, caused a lot of pain in others; probably the majority, with these ineffective methods. Remember, during this period both here and in Europe men were being diagnosed with more advanced stages of the disease. The diagnostic methods then were DRE and PAP, neither one very effective in establishing the presence of early disease. Bone scans did not have or presently have the power to identify micrometastasis. Ultrasound was not available during the early part of this period.

The historical lesson to learn from this in the U.S. is that conclusions derived from this period represent attempts to treat more advanced disease. All early work done with hormonal suppression for example is based on very advanced disease and the persistent conclusion as we all know, is that hormonal suppression is effective for 18 to 24 months, then patients become refractive. Are the rest of the conclusions derived from this period as mistaken as it is this example? Some are indeed.

There is no question that even though surgical methods have greatly improved because of better equipment, anesthetics and surgical skills, urology uses a fudge factor to ameliorate side effects. Side effects from surgery can't be ignored. Propensity for erectile dysfunction is high, very high. Incontinence although improved, remains relatively high. Many men go into surgery without the understanding of what it could do to them. This needs improvement and applies to many other less invasive treatments.

A study by Lu-Yao GL et al., Follow-up prostate cancer treatments after radical prostatectomy: a population-based study, provides some insight on the results of surgery during the later part of the period.
BACKGROUND: Radical prostatectomy is one of the most commonly used curative procedures for the treatment of localized prostate cancer. The probability that a patient will undergo additional cancer therapy after this procedure is largely unknown. PURPOSE: The objective was to determine the likelihood of additional cancer therapy after radical prostatectomy. METHODS: Data for this study were derived from a linked dataset that combined information from the Surveillance, Epidemiology, and End Results Program and Medicare hospital and physician claims. Records were included in this study if patient histories met the following criteria: (a) residing in Connecticut, Washington (Seattle-Puget Sound), or Georgia (Metropolitan Atlanta); (b) having been diagnosed with prostate cancer during the period from January 1, 1985, through December 31, 1991; (c) undergoing radical prostatectomy by December 31, 1992; and (d) having no evidence of other types of cancer. Patients were considered to have had additional cancer therapy if they had radiation therapy, orchiectomy, and/or androgen-deprivation therapy by injection after radical prostatectomy. The interval between the initial treatment and any follow-up treatment was calculated from the date of radical prostatectomy to the 1st day of the follow-up cancer therapy. All presented probabilities are based on Kaplan-Meier estimates. RESULTS: The study population consisted of 3494 Medicare patients, 3173 of whom underwent radical prostatectomy within 3 months of prostate cancer diagnosis. Although radical prostatectomy is often reserved for localized cancer, less than 60% (1934) of patients whose records were included in this study had organ-confined disease, according to final surgical pathology. Overall, the 5-year cumulative incidence of having any additional cancer treatment after radical prostatectomy reached 34.9% (95% confidence interval [CI] = 31.5%-38.5%). For patients with pathologically organ-confined cancer, the 5-year cumulative incidence was 24.3% (95% CI = 20.0%-29.3%) overall and ranged from 15.6% (95% CI = 9.7%-24.5%) for well-differentiated cancer (Gleason scores 2-4) to 41.5% (95% CI = 27.9%-58.4%) for poorly differentiated cancer (Gleason scores 8-10). The corresponding figures for pathologically regional cancer were 22.7% (95% CI = 12.0%-40.5%) and 68.1% (95% CI = 58.7%-77.1%). CONCLUSION: Further treatment of prostate cancer was done in about one third of patients who had a radical prostatectomy with curative intent and in about one quarter of patients who were found to have organ-confined disease. IMPLICATIONS: Given the common requirement for follow-up cancer treatments after radical prostatectomy and the uncertainties about the effectiveness of the various follow-up treatment strategies, further investigation of these treatments is warranted.

About the same time, Fowler FJ Jr, reported in "Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience"
To estimate the probabilities of complications and follow-up treatment, a sample of Medicare patients who underwent radical prostatectomy (1988 through 1990) was surveyed by mail, telephone, and personal interview. Respondents reported their current status with respect to continence and sexual function as well as post-surgical treatments they had to treat residual or recurrent cancer or surgical complications. Over 30 percent reported currently wearing pads or clamps to deal with wetness; over 40 percent said they drip urine when they cough or when their bladders are full; 23 percent reported daily wetting of more than a few drops. About 60 percent of patients reported having no full or partial erections since their surgery, and only 11 percent had any erections sufficient for intercourse during the month prior to the survey. Six percent had surgery after the radical prostatectomy to treat incontinence; 15 percent had treatments or used devices to help with sexual function; 20 percent report having had post-surgical treatment for urethral strictures. In addition 16 percent, 22 percent, and 28 percent reported follow-up treatment for cancer (radiation or androgen deprivation therapy) at two, three, and four years after radical prostatectomy. These estimates of complication and follow-up treatment rates are generally higher, and almost certainly more representative for older men, than estimates previously published. Patients and physicians may want to weight heavily the complications and need for follow-up treatments when considering radical prostatectomy for prostate cancer.

No bed of roses for treatments then, no bed of roses for treatments now. Those that proclaim the invincibility of treatments for prostate cancer always proclaim the importance of survival over quality of life issues. It is therefore a question of preference, which has to be addressed and understood by the individual patient. On the other hand, proponents of WW tend to proclaim the suffering caused by treatment's side effects while ignoring the fact that WW also conveys a high proportion of disease progression side effects. Urinary retention, uretric blockade, impotence, incontinence, bone pain etc. are very prevalent during progression of prostate cancer. Men need to understand all these facts in their decisions. In any way, it is not a clear-cut case for one side or the other.

The case for treatments is supported by study done by Lu-Yao GL et al., Population-based study of long-term survival in patients with clinically localized prostate cancer.
BACKGROUND: Choice of treatment in localised prostate cancer has been hampered by a lack of unbiased, representative data on outcome. Most existing data have come from small cohorts at specialized academic centres; precise overall and cancer-grade-specific data are not available, and the data are subject to differential staging bias. Randomised clinical trials have been undertaken, but the results will not be available for another decade. We have carried out a large population-based study to ascertain overall and prostate-cancer-specific survival in men treated by prostatectomy, radiotherapy, or conservative management. METHODS: Data for 59,876 cancer-registry patients aged 50-79 were analysed. We examined the effect of differential staging of prostate cancer by analysing the data both by intention to treat and by treatment received. Estimated survival was calculated by the Kaplan-Meier method. FINDINGS: By the intention-to-treat approach, 10-year prostate-cancer-specific survival for grade 1 cancer was 94% (95% CI 91-95) after prostatectomy, 90% (87-92) after radiotherapy, and 93% (91-94) after conservative management. The corresponding survival figures in grade 2 cancers were 87% (85-89), 76% (72-79), and 77% (74-80); those in grade 3 cancer were 67% (62-71), 53% (47-58), and 45% (40-51). Although the intention-to-treat and treatment-received analyses yielded similar results for radiotherapy and conservative management, the 10-year disease-specific survival after prostatectomy differed substantially (83% [81-84] by intention to treat vs 89% [87-91] by treatment received). INTERPRETATION: The overall and cancer-grade-specific survival found in this study differ substantially from those in previous studies. Previous studies that used a treatment-received approach have generally overestimated the benefits of radical prostatectomy. We found that grade 3 tumours are highly aggressive irrespective of stage.

Also Menon M, Should we treat localized prostate cancer? An opinion, supports the use of treatment in aggressive disease:
Localized prostate cancer is a progressive disease if left untreated. However, cancer-specific mortality is low in patients with moderately and well-differentiated prostate cancer treated with observation and delayed hormonal therapy, being 13% at 10 years and 20% to 30% at 15 years. By and large, radiation therapy does not appear to improve survival in these patients. With modern surgical techniques, mortality from prostate cancer is lowered by 23% to 65% in patients with moderately or well-differentiated tumors. However, the impact on relative cancer-specific survival is modest, since the mortality rate in untreated patients is low. The survival of conservatively managed patients with poorly differentiated prostate cancer is dismal: here radiation therapy or surgery significantly improves outcome. The QOL of patients with localized prostate cancer is significantly affected by the occurrence of distant metastasis. Metastatic rates are high in patients who are followed with observation and delayed endocrine treatment (19% to 85%). They were unable to deduce the effects of radiation therapy on grade-specific metastatic rates at 10 and 15 years. The only surgical series that addresses the issue shows a 50% to 80% reduction in metastatic rates. This results in an improvement in metastasis-free survival of 19% to 30%. The reduction in metastatic rates with surgery holds true for patients with poorly, moderately, or well-differentiated tumors. However, a significant proportion of the surgical patients were treated with adjuvant endocrine therapy, and it is impossible to identify the benefit from surgery and the benefit from adjuvant therapy. Radical prostatectomy improves survival in men who are 65 years or younger with moderately or well-differentiated adenocarcinoma of the prostate, and in men 75 years or younger who have poorly differentiated adenocarcinoma of the prostate. Its efficacy in reducing cancer-specific mortality in patients who have a survival expectancy of less than 15 years (older than 65 years) and moderately or well-differentiated adenocarcinoma of the prostate is less clear. Radical prostatectomy, with or without adjuvant hormonal therapy, decreases metastatic rates in men with a life expectancy of 10 years or more (age 75 years or younger) irrespective of tumor grade and, thus, should improve the QOL expectancy in these men. Nevertheless, between 20% and 60% of patients undergoing radical prostatectomy have biochemical recurrence, as defined by a detectable PSA, at 10 years of follow-up. This is worrisome and may portend clinical failure with longer follow-up.

In summary, all things said, there is no clear-cut, absolute, better way to treat or not treat prostate cancer. It is still a very personal decision in a road full of obstacles. Awareness about all these facts helps in defining our actual preferences. These are very personal things that dictate a decision.

What I believe is that the aggressive treatment system here is altering the natural course of prostate cancer by reducing the mortality rate of the disease. Something has changed. The disease is treated earlier and "cures" or freedom of disease have improved. The keyword is early and effective treatment. Let it be surgery, new radiation modalities or early hormonal intervention. Something has changed. This change translates to a reduced mortality rate for the past 10 years after a steady increase in the previous 25 years.  That is the current evidence....








D:\natural_history _untreated pca.doc

A review by Ralph Valle

Introduction
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.

Differentiation
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.

Grade III:
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.

Grade IV:
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.

Grade V:
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.

Gleason Score

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.

Discussion
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. . 

The Future
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/