The Incidence of Prostate Cancer.

Prostate cancer is the single most common non-skin malignancy for men in the United States. In 1996 there were approximately 317,000 reported new cases. Prostate cancer is the second most common cause of cancer deaths in men, second only to lung cancer with 41,000 deaths in 1996.  When we review the epidemiology of prostate cancer, we note that the prostate specific mortality is increasing at 1% globally yet there are predictions that in the United States there may be as much as a 37% increase in the Prostate cancer specific mortality by the year 2,000.  The reasons for this rapid increase mortality are varied.  One principle cause includes the changes in the demographics of the male population in the United States.  As the male population experiences a decline in the incidence of death from other diseases, many more men will live to an older age where prostate cancer is more prevalent.  Specifically, as the mortality from cardiovascular disease declines, we will see an increase in the life expectancy of American men.  It will be many of these men who will now be at a higher risk of morbidity and mortality due to prostate cancer.  
    

It was 1937 when the first tumor registries were started, which recorded the incidences of the different forms of cancer in the United States. In that year there were 30,000 newly diagnosed cases of prostate cancer reported. By 1950 the incidence of newly reported cases was 50,000. By 1973 it had climbed to 60,000. There was a steady yearly increase with 122,000 cases reported in 1991. It was in 1993 that we saw the first introduction of prostate specific antigen screening (PSA), and in that year there were 165,000 new cases of prostate cancer reported.  This trend continued, and in 1994,1995, and 1996 there were 200,000; 250,000; and 317,000 new cases of prostate cancer reported.  There is no debate that the use of digital rectal examination combined with the use of serum PSA testing has increased the detection of prostate cancer in this country. It is interesting to note however that the increase in prostate cancer cases began in 1950, well before the advent of the serum PSA testing.    
    

The incidence of prostate cancer varies in different regions of the world. Prostate cancer incidence in North America and Europe (Switzerland and Norway ) is far higher than in other parts of the world.  Conversely, the incidence of prostate cancer in Africa and Asia is comparably low when compared with other regions of the world. It is important to note that as populations migrate from low risk to areas to higher risk areas of prostate cancer, they increase their risk of developing the disease.  For example, the incidence of prostate cancer found in Africans is approximately 4 cases per 100,000 men. The incidence of prostate cancer found in African American men in the United States is approximately 160 cases per 100,000 men, a forty fold increase.  A similar trend is noted in reviewing the cases of prostate cancer in Asian men. The incidence of the disease in Asia is approximately 6 cases per 100,000 men, while the comparable measures of Asian American men is approximately 40 cases per 100,000 men. On Hawaii, halfway between the U.S. mainland and the Asian continent the incidence of prostate cancer for Asian American men living on the islands is 20 cases per 100,000 men.
    

The incidence of prostate cancer varies in different parts of the United States. For example, California has the highest number of newly reported cases of prostate cancer in the country.  Additionally, California has the highest number of prostate cancer deaths per year with an average of 24 deaths per 100,000 men. (U.S. average is 17/100,000).  The prostate cancer specific mortality; i.e. the number of men who actually die from the disease each year, ranks California higher than Sweden and Norway which have the highest prostate specific mortality in the world, those nations both experiencing approximately 22 deaths per 100,000 men.
    

Additionally, the incidence of prostate cancer varies among the different ethnic groups in the United States. It is generally accepted that the incidence of prostate cancer is almost 40% higher, stage by stage, among African American men versus Caucasian men. Hispanic men have a slightly lower rate than Caucasians men. The lowest rate of prostate cancer in the U.S. occurs in Asian American men, who generally have a 4 fold decrease in prostate cancer rate when compared with African American men.  Prostate cancer specific mortality tend to follow the same trends.  For example in Santa Clara County from 1988 to 1991 the specific mortality among African American men, was 59 deaths per 100,000 men. The prostate cancer death rate for Caucasian men, Hispanic men and Asian men in the county was 24,19 and 13 respectively. Compare these statistics with Japan and Africa where the prostate cancer specific mortality is approximately 4 deaths per 100,000. Note also, that the prostate cancer specific mortality among African American and Caucasian men in Santa Clara County is higher than the highest country in the world (Sweden, with 22 cases per 100,000 men).

Etiology of Prostate Cancer     

The underlying cause(s) for the development of prostate cancer is still unknown.  As the search continues to define the etiology of prostate cancer, it becomes clear that there are likely multi-variant factors involved in the development of the disease. These factors will likely involve both host factors as well as environmental factors.
    

The most reliable host factor critical in the development of prostate cancer is age. Ninety nine percent of the men affected with clinically significant (detectable) prostate cancer are age 50 years and older. There is also an increase in the presence of prostate cancer as a man ages.  For instance, in many autopsy series where prostates were examined from men who had died of
other causes, as many as 40% of the men by the age of 70 years had at least one focus of low grade prostate cancer present in the specimens reviewed.
    

Benign Prostate Hypertrophy (BPH) is a non life threatening form of overgrowth of the prostate gland.  BPH tends to occur in men over 50 years of age. BPH may also present many of the same symptoms of prostate cancer.  However, it is important to note, however, that BPH is not a precursor for the development of prostate cancer.
 
   

Reviewing the incidence and behavior of prostate cancer highlights the importance of the host race in the development of the disease. The reason for these ethnic variations in this disease are yet unknown. The answer may turn out to be different ethnic predilections for the chromosomal deletions known to be related to the development of prostate cancer. In 1993 Dr. Patrick Walsh at John Hopkins University documented the cases of men with prostate cancer directly under genetic influence. Men affected in this study group had an autosomal dominant transmission pattern for the development of prostate cancer. It is believed that as much as 4% of prostate cancer is transmitted this way. The vast majority of prostate cancer cases, however, occur without predictable antecedent genetic patterns. Additionally, it is known that if a man has a first degree relative affected (i.e. father or brother) that there is a three fold increase in the incidence of prostate cancer. There may also be ethnic difference in the immune systems response to these developing tumors which could account for both the differences in the incidence and behavior of this disease in different groups. This hypothesis is still in its testing stage.

Environmental factors which might play a role in the development of prostate cancer are many. The factor which has been consistently found to be a key in the development of prostate cancer is the ingestion of dietary fat. In populations where the ingestion of dietary fat is high, there is a higher incidence of prostate cancer. For example, if one plots the fat intake per capita by country against prostate cancer incidence we see that the higher fat-intake countries tend to have higher incidence of prostate cancer, as well as a higher prostate cancer specific mortality. What is interesting is that Japan, which has a low incidence of prostate cancer, has its highest incidence in the Kobe region, where the diet has been Westernized. It is not specially known exactly what quantities of dietary fat is needed to increase the risk of prostate cancer. It has been documented that laboratory animals fed a controlled low and high fat diets, that the animals fed high fat diets, develop prostate cancer at a higher rate.
    

The environment as a factor for the development of prostate cancer is underscored by regional differences in the incidence of prostate cancer. There have been no conclusive studies which identify any category of environmental substance(s) which are causative in the development of prostate cancer. Studies of cadmium (used in the production of batteries) have not proven a link to the development of prostate cancer. Zinc, which has its highest concentration in the body in the prostate gland, has also not been found to be causative in the development of prostate cancer. As prostate cancer is most likely related to the host environment interplay, it will be exceedingly difficult to isolate any single environment promoter for the development of prostate cancer.  

The Prostate Gland.
    
The prostate gland is a soft tissue organ which is located at the base of the bladder. Its major contribution is the provision of 90% of the ejaculatory fluids. The principle function of the ejaculatory fluid is to provide energy sources in the form of complex sugars to the ejaculate to nourish sperm. The ejaculate also provides liquefying enzymes which facilitates migration of sperm through the vaginal and cervical canals.       
                              
The prostate gland is composed of two major regions. The outermost region of the prostate gland is the capsule. The capsule consists of primary smooth muscle cells. It is in the capsule of the prostate gland that most (95%) prostate cancer originate (see Fig 1). The central region of the prostate gland is the transition zone. The transition zone is composed of two principle cell types. The smooth muscle cells, and the glandular epithelial cells. It is the overgrowth of these two cell types which are largely responsible for the development of BPH.    
    

The signs and symptoms of both prostate cancer and BPH are very similar, due to the similar position of the involved prostate gland on the outflow of urine. The symptoms are referred to as obstructive voiding symptoms. Since BPH remains more prevalent than prostate cancer, the vast majority of men with obstructive voiding symptoms will develop their symptoms on the basis of BPH rather than prostate cancer.
    

The position of the prostate gland in the low pelvis in front of (anterior to) the rectum allows easy examination of the gland during a physical exam. This position of the prostate gland also allows easy access for imaging with ultrasound probes and biopsy studies

Symptoms and Signs of Prostate Cancer. 

In the majority of men, the detection of prostate cancer occure in men who are asymptomatic. Those men who are present with the symptoms generally complain of a decreased urinary stream. The affected men may also have urinary urgency, urinary frequency or increase in nighttime voiding (nocturia).
   

When prostate cancer has spread beyond the confines of the prostate gland, the patient will show signs of fatigue, weakness and diffuse bony pain. The most important physical sign of prostate cancer is an abnormality in the prostate examination. The test performed by physicians to examine the prostate gland is called the digital rectal examination (DRE). The prostate gland should feel like the consistency of the palm of the hand. If the prostate has a nodule, an area of firmness or is asymmetrical, these represent changes in the gland that should be investigated. The primary care physicians now focus on these changes in the gland consistency, and have improved the detection of prostate cancer.
   

The vast majority of prostate cancer patients have little or no symptoms of the disease. Men who present with prostate cancer which is still confined to the prostate gland will present with obstructive voiding symptoms. These symptoms include a decreased force of their urinary stream, urinary urgency and frequency as well as incomplete bladder emptying with voiding. They may also notice that it takes a longer period of time to get their stream started, so called hesitancy. Men who are affected by prostate cancer which has already spread beyond the confines of the prostate gland may additionally experience easy fatigue, weakness and bony pain.         


Diagnostic Test.

The most important test in the early detection of prostate cancer is measurement of the serum prostate specific antigen (PSA). PSA is an enzyme which is made by glandular epithelial cells of the prostate gland.  It is released into the bloodstream in the presence and absence of prostate cancer. When prostate cancer is suspected, the release of the PSA into the bloodstream is increased. The normal range of PSA is 0.0-4.0 ng/dl. When the serum PSA is higher than 4.0 ng/dl, one possible cause is prostate cancer. Other causes for the increase in the release of PSA are BPH, prostate infection, prostate infraction, prostate stones, prostate manipulation, and ejaculation. Due to the non specific nature of what the meaning of an elevated PSA truly indicates, there has been some controversy regarding the usefulness of PSA. Recent advances in the use of combined digital rectal exam with serum PSA have improved the accuracy of PSA meaning. For instance, if a practitioner detects both an abnormality in the DRE, as well as the serum PSA, the ability of PSA to detect a true cancer is enhanced 50%.
   

New strategies for the use of the serum PSA are evolving. Patients now can have their PSA velocity measured to determine the possible need for a prostate gland biopsy. PSA velocity measures PSA at a particular point in time. The normal rate of increase in the PSA is no more than .7ng/dl per year. If a patient has a greater than .7ng/dl increase in his PSA in one year, this represents an abnormal PSA velocity. This strategy can then be used to more accurately predict the need for prostate biopsy.
   

Additionally, the enlargement of the prostate gland will lead to an increase in the release of PSA. Therefore, men with very large prostate glands may have a predictable increase in the of the released serum PSA. This concept of  predictable increase in the serum PSA is known as PSA density. This technique can also more specifically select men who should proceed with prostate biopsy.
   

The most recent test using PSA includes the use of measuring free and bound forms of PSA (this test is called PSA 11). It is known that PSA serum exist in two forms, free PSA and bound PSA (bound to alfa 1antichymotypsin ). The bound form of PSA, is more commonly found in patients affected with prostate cancer. Therefore, the more free PSA, the more likely the patient is affected with a benign prostate process. This test will more accurately assess the need for prostate biopsy.  
   

The use of prostatic acid phosphatase (PAP) and alkaline phosphatase have all but been supplanted by the use of PSA in the detection of and monitoring of prostate cancer. Many times complete blood counts are still useful in more advanced disease when considering the prognosis. It has been found that anemia may occur in many cases of extensive bony disease.
   

The most useful imaging study in the treatment of prostate cancer is the transrectal ultrasound (TRUS). Prior to the availability of TRUS, the vast majority of prostate cancers were diagnosed by transperineal or transrectal aspiration of the prostate gland. Many of these procedures were accompanied by hospitalization and the need for significant amounts anesthetic support. The histologic diagnosis of prostate cancer through the collection of specimens was difficult. The use of TRUS gives us a better understanding of the different zones of the prostate, and with the spring loaded gun, we can perform a sextant biopsy of the prostate gland in five minutes, with no anesthesia. The histologic diagnosis of prostate cancer is more easily made on the thin core biopsy tissue. The TRUS guided prostate biopsy is a minimally invasive examination well tolerated by patients, with a low rate of side effects (mostly 24 hours of minor hematuria).
   

TRUS can be used as a localizing tool to locate and guide the biopsy of an otherwise non palpable prostate tumors. TRUS is useful in quantifying the volume of the tumor which can be valuable in determining management options in selected patients. In addition, TRUS can be used to determine the presence or absence of extracapsular disease. TRUS may also be used to biopsy disease if it is suspected in the seminal vesicles or the periprostatic spaces. This can more accurately guide a patient  options for those patients with high volume disease who are selecting surgical management, but who are suspected of harboring extracapsular disease. The use of either computerized tomograhy (CT) scans or magnetic resonance imaging (MRI) have not routinely been found useful in managing prostate cancer.  Magnetic resonance spectroscpy (MRS) is experimental now, but may have a place measuring citrate levels within the prostate to distinguish prostate cancer from BPH.
   

The use radionucleide bone scans is still useful in determining the presence or absence of skeletal metastasis. It is now known that if serum PSA is less than 10 ng/dl that the likelihood of harboring skeletal metastasis is exceedingly low. Therefore in this situation a bone scan is no longer routinely ordered on all patients prior to treatment of their prostate cancer. In patients with high grade tumors (Gleason 7-10), high volume tumors, or any bony pain at the
time of presentation of the disease, the use of a bone scan may be indicated regardless of the PSA level.


Staging.

Once a man is diagnosed with prostate cancer, the extent of the cancer must be determined. The determination of where the tumor is, is called staging the cancer. Prostate cancer has 4 major stages.

STAGE A (T1):Tumor detected by PSA alone.                              

                     Tumor confined to the prostate gland.
                     Tumor confined to < .5 cm on rectal exam.

STAGE B (T2): Tumor confined to prostate gland but > .5 on a rectal exam.
                      Tumor palpable on both lobes of the prostate gland.

STAGE C (T3): Tumor palpable outside the confines of the prostate gland.
                      Tumor found outside the prostate gland on Imaging studies

STAGE D (T4): Tumor in the lymph nodes.
                       Tumor adjacent to organs (spine, liver, etc.)
   
The staging of a cancer is divided into 2 parts. The initial staging is called clinical staging. This includes the physician’s determination of the stage without invasive proof of the stage. The definitive staging is called pathologic staging, and this require an actual tissue biopsy for proof.

Grade.

The grade of a prostate cancer refers to the expected potential of the tumor to metastasize (spread). So called low grade, well differentiated, tumors have a low malignant potential, or a low potential to metastasize. High grade, or poorly differentiated tumors, has a high potential to metastasize. The principle grading system for prostate cancer is called the Gleason grading system. This system utilizes common known patterns of prostate cancer cells, and describes each pattern with a number from 1-10. The higher the number the higher the malignant potential. For example, a total Gleason score of 3, is considered to be a low malignant tumor. In contrast, total Gleason score of 8 would be considered a highly malignant tumor.
       

Similar tumor behavior can be predicted by studying the chromosome of the prostate cancer cells. Prostate cancers which are populated by cells which contain the normal amount of chromosomes, or DNA, are called diploid tumors. These tend to be well differentiated, low malignant potential tumors. The opposite of these well differentiated diploid tumors are the aneuploid
Tumor,s. These aneuploid tumors have an uncountable amount of chromosome strands of DNA, and are poorly differentiated, and highly malignant potential tumors.
   

Tumor volume is also very important in determining tumor behavior. It is believed that tumor volumes measured by transrectal ultrasound of less than 0.5 cc are well differentiated, low malignant potential tumors. Tumors which measure greater than 3 cc tend to behave like poorly differentiated, highly malignant tumors.
   

The zone of origin of the prostate tumor is also important in determining the malignant potential of a prostate cancer. Most prostate cancers originate in the peripheral zone of the prostate gland. These tumors generally close to the edge of the prostate gland, and the neural vascular bundles of the prostate gland. This position helps the peripheral tumors gain access to the outside of the prostate gland at a higher frequency than more centrally developing tumors. The central portion of the prostate gland is called the transitional zone. Tumors which arise in the transitional zone can obtain substantial size before they spread outside the gland.
   

With the use of Gleason scoring, tumor ploidy, tumor volume and using the location of the tumor, we can more accurately determine the malignant potential of a tumor. These tools are invaluable in making decisions regarding the treatment of prostate cancer.

Prognosis.

It has long been known that most men with prostate cancer will die with their tumor, and not from their tumor. This fact stems from the presence of microscopic prostate cancer cells which exist in as many as 50% of men over 80 years old. In the past these microscopic tumors have been referred to as “latent” prostate cancer. Of course most men who are found to have prostate cancer are identified as a result symptoms (obstructive or irritate voiding symptoms), signs (abnormal rectal exam), or abnormal PSA test. These men are considered to have clinical prostate cancer. With the advent of serum PSA testing, many clinicians worried that PSA would detect many men with latent prostate cancer. This has not be found to be the case. Eighty five percent of men with elevated PSA levels as their only abnormality are found to have clinically significant tumors. It is also known that latent prostate cancer is a progressive disease, which if given enough time can threaten the host.
   

Stage A and stage B prostate cancers are believed to be curable. The overall survival rates for men treated with Stage A prostate cancer is approximately 94% at 10 years. The overall survival rate for men treated with Stage B prostate cancer at 10 years is between 85-90%. The overall survival rate of men treated with Stage D prostate cancer at 10 years is 10%.
   

These differences in survival underscore the need to detect prostate cancer early, if one is to have a reasonable chance of a cure. With the advent of serum PSA testing and digital rectal exam screening, we have seen a shift in the stage of prostate cancer presentation. Prior to 1990,  the vast majority of American men were diagnosed with Stage D disease. Due to the new early detection techniques and strategies, most men now diagnosed with Stage A or B disease.
   

Treatment.

There are multiple good options for the treatment of prostate cancer. The selection of which is the most appropriate option for any given individual patient is dependent upon the desire of the patient to achieve either palliation (slowing down of the cancer process-remission), or cure. Only Stage A and B prostate cancers are thought to be curable.
   

One new option in the management of prostate cancer is the use of observation strategy. This involves the use of serial digital rectal exam, serum PSA testing (with occasional transrectal ultrasound) to monitor the growth of the tumor. Presumably, if the tumor does not grow, then the patient can continue to follow his cancer without intervention. Only if the tumor begins to grow, then the patient would exercise the option for treatment. There is a chance that the tumor may increase in stage or grade during the observation period, therefore if the a patient is not compliant with this strategy, he should be immediately enrolled in a more conventional treatment plan.

The curative strategies for prostate cancer include the use of radical prostatectomy or definitive radiation therapy.


Radical Prostatectomy.

Radical prostatectomy represents the oldest form of treatment the localized prostate cancer. The goal this operation is to remove all the cancer which is confined to the prostate gland, thereby rendering the patient cured. Radical prostatectomy involves total removal of the prostate gland. In localized disease, this operation is associated with a 80-90% cure rate. The operation has been improved over the years, to where now there is very little operative time, and very little blood loss. The incontinence rate is only 2-4% of men. Incontinence is described as requiring at least one urinary collection pad in the underwear to collect urinary leakage, nine months after surgery. Today even when men develop incontinence, the option of Contigen implantation can correct the leakage that some men experience. If this fails, the use of an AMS artificial sphincter can be used to correct urinary incontinence. Radical prostatectomy performed with cavernous nerve sparing technique can greatly reduce the need for the correction of impotence. Even in the event that a man becomes totally impotent following radical prostatectomy, either the use of penile medications, vacuum erection devices, intraurethral  medications or the implantation of a penile prosthesis can be used to completely correct any erection dysfunction (impotence).



Radiation Therapy.

Radiation therapy is also a good option for men with localized, curable prostate cancer. The goal of this radiation therapy is to cause programmed prostate cancer cell death over time. This treatment can be delivered with either external beam format, or by the use of intraprostatic seed implants. Although in the past the external beam technique was associated with a lower cure rate that surgical therapy cure rates, this may not be true with the use of intraprostatic seed therapy. Radiation therapy is an excellent option for treating men with localized cancer who have other medical co-morbidities which would make the use of surgery dangerously prohibitive. The rate of incontinence and impotence are lower than with radical prostatectomy, however when present, these complications can be somewhat harder to deal with.
  

When prostate cancer has spread outside of the prostate gland, palliative therapy is used to slow the progression of the disease. This type of treatment can often lead to survival measured in decades. The basis of palliative therapy is in the understanding that the prostate cancer cell are stimulated to grow by the male hormone, testosterone. This hormone can be deleted by removing its source, the testicles. This procedure is called orchiectomy, and represents the most conventional method of dealing with dealing with metastastic prostate cancer. Additionally, today there are medications which can be used which block the release of testosterone from the testicles. These medications include Lupron, Zoladex and Diethylstilbesterol (DES). Recent studies indicate that the small amount of male hormone released from the adrenal gland may also be important in the stimulation of prostate cancers. The release of these male hormones may be blocked by medications called Flutamide, Casodex and Nalidrone.
   

In current practice it is common to base treatment decisions on both patient factors and tumor factors. For instance, one should take into account patient expected longevity before beginning any plan of therapy. Additionally, we must consider any concurrent illness (heart attack, stroke, or any other terminal illness) prior to making treatment decisions. For example, an 80 year old man with severe heart disease may be a candidate for only the most conservative forms of therapy. When considering tumor factors include tumor volume, ploidy, Gleason grade, and cancer stage. For example, a 51 year old man with a tumor volume of 1.0 cc, which is aneuploid, Gleason 8 and stage B (T2), would be an excellent candidate for aggressive intervention (surgery or radiation therapy). As you can imagine, when considering all of these variables you see why each prostate cancer treatment decision must be individualized.


Conclusion. 

    The incidence of prostate cancer has been increasing since statistics were first collected in the 1930s. Prostate cancer yearly case rates have been increasing even prior to the widespread use of screening programs using serum PSA testing. The etiology for prostate cancer is multi-factorial. These factors include age, ethnicity, diet and region of the world were the man lives. Fortunately the diagnosis of prostate cancer is the best it has ever been. This disease can now be reliably diagnosed with non invasive means. The treatment options now are very refined and offer men not only cure, but also a high quality of life after treatment. The most important aspect of management of prostate cancer lies in the individualized treatment plan for a particular patient.