Causes, Natural History & Diagnosis of Prostate Cancer

Prostate cancer is the second leading cause of cancer deaths among men in the United States. Yet, when detected in its early stages, prostate cancer can be effectively treated and cured. What are its causes and symptoms? How is it diagnosed? The following information should help answer such questions.

What is the prostate?
The prostate gland is a small, walnut-sized gland in men. It is located below the bladder and surrounds the upper portion of the urethra. The prostate gland lies in front of the rectum, and its posterior surface can be felt during a rectal examination. The function of the prostate is to secrete a fluid that makes up part of the semen. The prostate gland may be a source of many health problems in men, the most common being benign prostatic hyperplasia (BPH), prostatitis and cancer.

What is prostate cancer?
Prostate cancer is a significant health-care problem in the United States due to its high incidence. It is the most common cancer in men affecting approximately 189,000 American men each year with approximately 32,000 of these men dying each year. Prostate cancer is different from most cancers in that a large percentage of men may have a silent form of this cancer Ñ it does not cause symptoms or progress beyond the prostate gland. Sometimes this cancer can be small, slow growing and present limited risk to the patient. Clinically important prostate cancers can be defined as those that threaten the well-being or life span of a man.

What are the causes and risks associated with prostate cancer?
What causes prostate cancer is a subject of intensive research. It is likely that prostate cancer occurs due to many reasons. Predominately a disease of elderly men, the diagnosis of prostate cancer is rare before age 40 but increases dramatically thereafter. In the United States, it is estimated that one in 55 men between the ages of 40 and 59 will develop prostate cancer. This incidence climbs almost to one in seven for men between ages 60 and 79. This association is also reflected in mortality as prostate cancer accounts for 10.8 percent of cancer-related deaths in men between the ages of 60 and 79 and 24.6 percent in those over the age of 80.

Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality among men. There is, however, a notable variability in incidence and mortality among world regions. The incidence is low in Japan and intermediate in regions of Central America and Western Africa. The incidence is higher in North America and Northern Europe. Although some of these differences may be accounted for by differences in screening for prostate cancer and the risk of other diseases among world regions, it is likely that they can be accounted for, in part, by genetic predisposition as well as diet.

There are also ethnic determinants of risk. Blacks are in the highest risk group, with an incidence of 224.3 cases per 100,000 black men. The incidence in Caucasian and Asian men is considerably lower at 150.3 and 82.2 (per 100,000), respectively. In addition, blacks tend to present with more advanced disease and have poorer overall prognosis than Caucasian or Asian men.

Men with a family history of prostate cancer are at an increased risk of developing the disease. The risk correlates with the number of first-degree relatives (father, brother or uncle) affected by prostate cancer and the age at onset. Men with a family history of disease may have a risk of developing prostate cancer two to 11 times greater than men without a family history of prostate cancer.

There is also considerable evidence showing that prostate cancer is more common in men with a high intake of fat in their diets. The worldwide difference in prostate cancer incidence may be associated with dietary intake of soy proteins. In Asian countries such as Japan and the Republic of Korea where prostate cancer incidence and mortality are just a fraction of that in North America, soy consumption in the form of tofu, soymilk and miso is up to 90 times higher than that consumed in the United States. In a study of more than 40 nations, researchers found soy, on a per calorie basis, to be the most protective dietary factor. This protective role may be associated with two of soy's components, genistein and daidzein that may act as weak estrogens. Estrogens are female hormones that inhibit prostate cancer growth. Some experts have suggested that the worldwide differences in prostate cancer incidence may also be explained by the high intake of green tea by residents of Asia.

The intake of other certain dietary factors may also reduce the risk of developing prostate cancer. Such substances include lycopene, selenium and vitamin E. Cooked tomatoes are rich sources of the carotenoid lycopene. Lycopenes are antioxidants that may protect cells from becoming cancerous. Several studies have shown that the likelihood of developing prostate cancer is reduced by high intake of lycopene. Researchers found that men ingesting two or more servings of tomato sauce per week had a 36 percent reduction in cancer risk compared to those who did not. Selenium intake has also been reported to lower prostate cancer risk. In a clinical trial designed to determine if selenium could lower skin cancer recurrences, men who took selenium had a 63 percent reduction in prostate cancer incidence compared to those who took a sugar pill (placebo). Attention has also focused on vitamin D's effect on the prostate. Epidemiologic evidence shows an inverse relationship between prostate cancer risk and ultraviolet radiation, the primary source for vitamin D production. This observation has led some to suggest that higher rates of prostate cancer in the elderly may be partly due to decreased sun exposure or a decline in the body's ability to make vitamin D with aging.

Finally, the correlation of vasectomy and prostate cancer risk remains controversial. Although some studies have suggested that men who have undergone a vasectomy are at an increased risk of developing prostate cancer, many other studies have failed to show such a correlation.

What are the symptoms of prostate cancer?
In its early stages, prostate cancer often causes no symptoms. When symptoms do occur, they may include any of the following: dull pain in the lower pelvic area; frequent urination; problems with urination such as the inability, pain, burning, weakened urine flow; blood in the urine or semen; painful ejaculation; general pain in the lower back, hips or upper thighs; loss of appetite and/or weight; and persistent bone pain.

How is prostate cancer diagnosed?
Currently, digital rectal examination (DRE) and PSA tests are used for prostate cancer detection. The age at which time screening for prostate cancer should begin is not known with certainty. However, most experts agree that healthy men over the age of 50 should consider prostate cancer screening with a DRE and PSA test. Screening should occur earlier, at age 45, in those who are at a higher risk of prostate cancer such as black men or those with a family history of prostate cancer.

DRE: Is performed with the man either bending over, lying on his side or with his knees drawn up to his chest on the examining table. The physician inserts a gloved finger into the rectum and examines the prostate gland, noting any abnormalities in size, contour or consistency. DRE is inexpensive, easy to perform and allows the physician to note other abnormalities such as blood in the stool, which might allow for the early detection of rectal or colon cancer. However, DRE is not the most effective way to catch an early cancer so it should be combined with a PSA test.

PSA test: Is usually performed in addition to DRE and increases the likelihood of prostate cancer detection. The test measures the level of PSA, a substance produced only by the prostate, in the bloodstream. Very little PSA escapes from a healthy prostate into the bloodstream, but certain prostatic conditions can cause larger amounts of PSA to leak into the blood. One possible cause of a high PSA level is benign (non-cancerous) enlargement of the prostate, otherwise known as BPH. Prostate cancer is another possible cause of an elevated PSA level. The frequency of PSA testing remains a matter of some debate. The American Urological Association (AUA) encourages men to have annual PSA testing starting at age 50. The AUA also recommends annual PSA testing for men over the age of 40 who are African-American or have a family history of the disease (for example, a father or brother who was diagnosed with prostate cancer). Some experts have suggested that men with an initial normal DRE and PSA level of less than 2.5 ng/ml can have PSA testing performed every two years. Recently, several refinements have been made in the PSA blood test in an attempt to determine more accurately who has prostate cancer and who has false-positive PSA elevations caused by other conditions like BPH. These refinements include PSA density, PSA velocity, PSA age-specific reference ranges and use of total-to-free PSA ratios. Such refinements may allow for improved increased ability to detect cancer.

Currently, it is recommended that both a DRE and PSA test be used for the early detection of prostate cancer. It is important to realize that in most cases an abnormality in either test is not due to cancer but to benign conditions, the most common being BPH. For instance, it has been shown that only 18 to 30 percent of men with serum PSA values between four and 10 ng/ml have prostate cancer. This number rises to approximately 42 to 70 percent for those men whose PSA values exceeding 10 ng/ml.

Biopsy: Prostate biopsy is best performed under transrectal ultrasound guidance using a spring-loaded biopsy device coupled to the transrectal probe, which is placed in the rectum. Patients are positioned on their side for this procedure. The physician will first image the prostate using ultrasound noting the prostate gland's size and shape and whether or not any other abnormalities exist, the most common of which are shadows which might signify the presence of prostate cancer. However, not all prostate cancers are visible. Using the spring-loaded biopsy device attached to the ultrasound probe, the physician will perform multiple biopsies of the prostate gland. Generally, six to 14 biopsies will be performed. Recently, many investigators have shown that performing more than six biopsies, especially in certain regions of the prostate gland, will improve the ability to detect prostate cancer. Each biopsy will remove a cylinder of prostate tissue approximately 3/4 inch in length and 1/16 inch in width. The entire procedure will take 20 to 30 minutes. The biopsy tissue taken will then be examined by a pathologist (a physician who specializes in examining human tissue to determine whether it is normal or diseased). The pathologist will be able to confirm if cancer is present in the biopsy tissue. If cancer is present, the pathologist will also be able to grade the tumor. The grade indicates the tumor's "aggression level" Ñ how quickly it is likely to grow and spread. The most popular prostate cancer grading system is the Gleason score system and is designated between two and 10. Scores of two to four designate low aggressiveness, five to six mildly aggressive, seven moderately aggressive and scores of eight to 10 highly aggressive.

Although transrectal ultrasound guided prostate biopsy is usually very well tolerated, approximately 20 to 25 percent of those undergoing the procedure may find it painful. Injecting local anesthetics into the area before biopsy may minimize this discomfort. Blood in the ejaculate (hematospermia) and blood in the urine (hematuria) are common, occurring in approximately 40 to 50 percent of patients. High fever is rare, occurring in only 3 to 4 percent of patients. Antibiotics and enemas are usually given at the time of the procedure to prevent infection.

Why is prostate cancer staged? Once prostate cancer has been diagnosed by a prostate biopsy, the physician seeks to stage the disease; that is, to determine the extent of the cancer (i.e., the "T" stage) and whether it has spread to the lymph nodes and/or the bones. The T stage is determined mainly by the DRE and can be divided into the following categories:

• T1: Doctor is unable to feel the tumor or see it with imaging (e.g., transrectal ultrasound)
• T1a: Cancer is found incidentally during a transurethral resection (TURP) for benign prostatic enlargement. Cancer is present in less than 5% of the tissue removed
• T1b: Cancer is found after TURP but is present in more than 5% of the tissue removed
• T1c: Cancer is found by needle biopsy that was done because of an elevated PSA
• T2: Doctor can feel the tumor when a digital rectal exam (DRE) is performed but the tumor still appears to be confined to the prostate
• T2a: Cancer is found in one half or less of only one side (left or right) of the prostate
• T2b: Cancer is found in more than half of only one side (left or right) of the prostate
• T2c: Cancer is found in both sides of the prostate
• T3: Cancer has begun to spread outside the prostate and may involve the seminal vesicles
• T3a: Cancer extends outside the prostate but not to the seminal vesicles
• T3b: Cancer has spread to the seminal vesicles
• T4: Cancer has spread to tissues next to the prostate (other than the seminal vesicles), such as the sphincter, rectum and/or wall of the pelvis

To determine if the cancer has spread to the lymph nodes or bones, the physician may order a CT scan of the pelvis or a bone scan. This is only done when the physician deems the cancer to be very serious.

Prostate cancer represents a spectrum of disease. Although some cancers may grow so slowly that treatment may not be needed, others can represent a threat to life. Determining the need for treatment can be a complex decision. Initially, the need for treatment should be based on the stage and grade of the cancer as well as the age and health of the patient. Many physicians have sought to devise risk assessment schemes that predict the likelihood of disease recurrence if patients are treated and progression or significant growth of their cancer if they undergo initial surveillance or watchful waiting. By combining many types of information (i.e., serum PSA level and cancer grade, stage and volume), patients can be advised of the aggressiveness of their cancer and the need for and types of treatment available. Certain imaging tests, such as a radionuclide bone scan, CT scan or MRI, may need to be done to better assess whether the cancer is still confined to the prostate or has spread elsewhere in the body. When prostate cancer spreads (metastasizes) it is usually to the lymph nodes or bones. Not all men with prostate cancer need to undergo imaging tests as the risk of spread to other organs can be estimated on the basis of serum PSA levels and cancer grade. It is reasonable to omit the bone scan in patients with newly diagnosed, untreated prostate cancer, who have no symptoms from their cancer and have serum PSA concentrations less than 20 ng/ml and certainly in those with serum PSA concentrations less than15 ng/ml. Similarly, a pelvic CT scan or MRI may not be necessary in men with lower grade cancers, cancers still confined to the prostate and serum PSA values less than 25 ng/ml.

Frequently asked questions:

Can prostate cancer be prevented?
No. However, you can take measures to reduce the risk by maintaining your health in general Ñ healthy diet, being physically active and visiting the doctor on a regular basis. Clinical studies are ongoing which are testing the ability of some agents like vitamin E and selenium to prevent prostate cancer.

What is the outlook for prostate cancer?
The number of men diagnosed with prostate cancer remains high. However, survival rates are improving. It is estimated that 89 percent of men diagnosed with the disease will survive at least five years, while 63 percent will survive 10 years or longer.