How Prostate Cancer is Diagnosed

Man Receiving Medical Scan for Prostate Cancer Diagnosis
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A diagnosis of prostate cancer is often first suspected when a screening tests such as a serum PSA or digital rectal exam are abnormal. Diagnostic tests may then include an MRI or MRI-TRUS fusion with targeted biopsy or an ultrasound-guided random 12-core biopsy. Based on biopsy findings, a Gleason score is used to describe the aggressiveness of the tumor, and further tests, such as a CT scan, MRI, bone scan, or PET scan may be done to accurately stage the tumor.

Since prostate cancers can differ very significantly in their tendency to grow or spread, staging is important in choosing the best treatments, determining the risk of recurrence, and estimating the prognosis of the disease.

Screening Tests

The vast majority of prostate cancers are discovered on screening tests, before any signs and symptoms occur. There are two screening tests, that are best when used together (either of these tests should not be used alone). In general, screening is recommended for men beginning at the age of 50 (though this is an area of active debate), though men who have risk factors for prostate cancer, such as a family history of the disease, are usually adviced to begin testing earlier than this.

Screening tests cannot diagnose prostate cancer, but rather let physicians know if further testing to look for the disease is needed.

In recent years there has been considerable controversy surrounding screening, since it's thought that PSA testing results in significant overdiagnosis and overtreatment of the disease.

That said, prostate cancer remains the second leading cause of cancer-related deaths in men, and the disease may be easier to treat in the earlier stages of the disease.

2018 review published in JAMA for the U.S. Preventive Services Task Force concluded that PSA screening may reduce deaths due to prostate cancer, but at the risk of false-positive results, biopsy complications, and overdiagnosis.

It's not certain at this time whether there are long-term survival benefits for actively treating prostate cancer detected by PSA screening, but it is known that these treatments can have significant urinary and sexual side effects. What this boils down to is that screening has the potential to save lives, but we don't currently have evidence that it saves lives, at least from a statistical standpoint. At first glance, this potential to save lives might have men wondering why anyone would choose not to screen. The reason, however, is that screening with the hope of saving lives will mean that many men will unnecessarily need to cope with treatment side effects such as erectile dysfunction and urinary problems even though their prostate cancer would not have grown or spread. Those who choose to have the test should understand the limitations of the test and have a thoughtful discussion with their doctor. 

Risks of Screening

It's important to understand the limitations of screening, as screening (or at least the tests that may be done to followup abnormal values) can have risks. If a PSA and/or digital rectal exam is repeatedly abnormal (testing should not be done for a single abnormal PSA value), further testing can involve either targeted or random biopsies.

These biopsies can sometimes result in complications requiring hospitalization, and rarely, death.

Prostate Specific Antigen (PSA) Testing

The PSA test is a simple blood test (drawn from your arm) that determines the level of prostate specific antigen (PSA) in the blood. PSA is a protein secreted by prostate cells and is very specific for prostate tissue. It is not a perfect test, in that there are causes for elevated levels other than prostate cancer, such as benign prostatic hyperplasia (BPH) and prostatitis, and PSA levels also increase with age. Similarly, some men with prostate cancer may have normal PSA tests, and some medications for BPH, as well as obesity, can cause decreased levels of PSA.

There are ranges of PSA that are considered normal and high, but the most important factor in interpreting the test (unless it is very high) is a change in the value over time. In other words, a PSA level that is increasing is often more meaningful than the absolute value of the test. In the past, an arbitrary cut-off of 4 nanograms per milliliter was used to separate normal and possibly abnormal PSA levels. That said, more than half of the time when a level is greater than 4, the cause is not cancer. Similarly, prostate cancer may be present even with a level less than 4 ng/ml.

Variations of PSA include:

  • PSA velocity: This number describes the change in PSA over time, and a rapid increase in the value of PSA suggests cancer. It's not known how helpful this test is at the current time.
  • Free PSA: Free PSA measures the amount of PSA in the blood that is not bound to proteins divided by the total level of PSA. If this number is less than 10 percent, the tumor is more likely to be cancer, and if greater than 25 percent, more likely to be benign. Unfortunately, many levels will fall between 10 and 25 percent and the significance of these values is unknown.
  • PSA density: This number compares the PSA to the size of the prostate on ultrasound or MRI, with a higher PSA density more likely to be cancer (prostate cancers produce more PSA than benign prostate cells). The test, however, is fairly impractical as it requires an ultrasound of the prostate.
  • Age-specific PSA: This test separates out expected PSA levels based on age, but may miss some prostate cancers.
  • Pro-PSA: This test may help distinguish between a PSA of 4 to 10 that is related to prostate cancer vs a level that is due to BPH. It may be helpful when deciding if a biopsy is necessary.

Digital Rectal Exam (DRE)

In a digital rectal exam (DRE), a doctor inserts a gloved, lubricated finger into the rectum to palpate the prostate gland and check for lumps, hardness, or tenderness. Since the prostate gland lies just in front of the rectum, the prostate is fairly easy to palpate by this approach. While the procedure can be somewhat uncomfortable, may cause a sensation of needing to urinate, and can be embarrassing, it's very important to use this test along with the PSA.

Tumor Markers

Biomarkers are substances that are either produced by a prostate cancer or by the body when a prostate cancer is present. Two of these tests include the 4Kscore and the prostate health index (PHI); tests that can be used to predict which men may develop prostate cancer or high-risk prostate cancer.

Diagnostic Tests and Procedures

If a PSA or DRE is abnormal, further testing may be needed to determine if a prostate cancer is present, and if so, the aggressiveness of the cancer. As noted earlier, the change in PSA levels rather than the absolute level is important in determining if a biopsy should be performed. Options include:

Transrectal Ultrasound (TRUS)

A transrectal ultrasound (TRUS) may be used to help identify abnormalities. This approach may be used to calculate PSA density, or combined with MRI to determine areas that should be biopsied (see below). If a TRUS is abnormal, a biopsy is still needed to determine if any regions that appear abnormal are actually cancer.

Random 12-Core Biopsy

If a PSA is persistently abnormal, or abnormalities are felt on a DRE or seen on TRUS, one approach to determining if a cancer is present in a random 12-core biopsy.  In this procedure, samples are taken from 12 random areas in the prostate gland and are looked at under the microscope to determine if prostate cancer cells are present.

The procedure is usually done as an outpatient. Men are placed on a clear liquid diet and given an enema before the procedure. While lying on their left side with a full bladder, the rectum is numbed locally with lidocaine where the biopsies will be done. A thin ultrasound is inserted into the rectum to visualize the prostate throughout the procedure. After the anesthesia is working, 12 to 14 samples are taken by inserting thin, hollow needles into the prostate gland. 

The procedure takes roughly 20 to 30 minutes and men may experience some rectal soreness for a few days after the procedure. Some men experience light bleeding, or note spots of blood in their stool, urine, or semen for a few days. Warm soaks and compresses may alleviate some of the discomforts. Results will be available a few days later and may be discussed in person or over the phone.

MRI with Targeted Biopsy

Since random biopsies may miss some areas of cancer, and also expose people to biopsies of normal tissues, modifications of the biopsy technique above have been developed. Multiparametric MRI (mp-MRI) is a special type of MRI used to detect abnormalities in prostate tissue. The procedure is similar to that above, but an MRI is done to define any suspicious regions. Biopsies are then limited to these abnormal appearing regions that can be selectively biopsied. It's thought that this approach may help reduce the risk of overdiagnosis and overtreatment of prostate cancer. This procedure is not available at all cancer centers and requires specialized training.

MRI Fusion Biopsy

An MRI fusion biopsy is similar to the multiparametric MRI discussed above, but used a combination of MRI and transrectal ultrasound (MRI-TRUS fusion technology) to look for abnormal areas in the prostate. It's also thought that selective biopsies done based on the information obtained will improve the accuracy of diagnosis. As with multiparametric MRI, the procedure is not available everywhere and requires specialized training.

Prostate Cancer Gene 3 (PCA3) RNA Test

If a PSA is persistently elevated, but a biopsy does not reveal cancer, the gene test gene 3 (PCA3) RNA  may be recommended. This test measures the level of PCA3 RNA in the urine after a digital rectal exam. If the test is elevated, a repeat biopsy may be recommended.

Staging Tests

The tests above may confirm a diagnosis of prostate cancer, but do not tell physicians how aggressive the tumor is or how far it has spread. Keep in mind that many prostate cancers are non-aggressive and would never cause a problem if left alone. Based on the Gleason score, further tests may be done to further stage the tumor. Prostate cancer typically first spreads to the tissues immediately adjacent to the prostate, including the seminal vesicles, rectum, bladder, and lymph nodes. Prostate cancer also has a very strong tendency to spread to bones. This is most common in the lower spine, the pelvis, and the upper legs, though prostate cancer can spread to bones anywhere in the body.

Lab Tests

The level of PSA is one factor that is included in staging. The blood test alkaline phosphatase may be increased if prostate cancer has spread to bones.

Imaging Tests

Imaging tests may be done to look for the spread of prostate cancer to nearby tissues, as well as distant tissues such as bone. These tests are often not needed for early prostate cancers or those with low Gleason scores (see below). Tests may include:

  • MRI: An MRI can be helpful in determining whether a cancer has spread to the seminal vesicles, lymph nodes, or other regions.
  • CT Scan: CT is used less often than MRI, but may be helpful for look for lymph node involvement.
  • Bone Scan: In a bone scan, a radioactive tracer is injected into the bloodstream, and imaging is done to look for uptake in bones that might signify bone metastases.
  • PET scan: A PET scan (positron emission tomography), is a special type of imaging test that looks at the "function" of tissue inside the body instead of structure alone. In this test, radioactive glucose is injected into the body. This glucose is taken up more readily by tissues that are actively growing (more active metabolically), such as cancer cells. Prostate cancer cells, unlike some other types of cancer cells, do not as readily take up radioactive glucose, and therefore are less likely to be found on a PET scan than some other cancers. To compensate for this, a special type of PET scan (such as an Axumin or C-11 choline PET scan) is often done.

Gene Testing

Recently, gene tests have begun to play a role in determining the aggressiveness of some prostate cancers, and it's thought that these tests will play an important role in both the diagnosis and staging of the disease in the future.

Stages and Grades

Once a prostate cancer is diagnosed, and tests are done to evaluate the extent and look for spread of the cancer, the cancer is assigned a stage based on the grade of the cancer, PSA levels, and the extent of the cancer.

Gleason Score Grading

Prostate cancer cells are given a grade between 3 and 5 based on their appearance under the microscope. A score of 3 would mean that the cells look very much like normal prostate cancer cells (well-differentiated) and a score of 5 would mean that the cells appear highly abnormal (poorly differentiated). To get the Gleason score, a score of 3 to 5 is given based on the appearance of the cells in two different areas of the tumor, to get a score of 6 to 10.

Gleason scores:

  • Gleason 6; A score of 6 defines a low-grade cancer in which the cells appear much like normal prostate cells. These tumors are unlikely to grow or spread.
  • Gleason 7: These tumors are considered medium grade cancers and the cells are moderately abnormal appearing.
  • Gleason 8 to 10: These tumors are considered high grade cancers and the cells appear very different from normal prostate cells. These tumors are more likely to grow and spread.

Grade Groups: Based on these scores, prostate cancers are often placed in groups called grades, and these grades are included in staging (below).

  • Grade Group 1: Includes Gleason 6 tumors
  • Grade Group 2: Includes Gleason 7 tumors (3 + 4 = 7)
  • Grade Group 3: Includes another type of Gleason 7 tumors (4 + 3 = 7)
  • Grade Group 4: Includes Gleason 8 tumors.
  • Grade Group 5: Includes Gleason 9 and Gleason 10 tumors.

TNM Staging

As with many other cancers, TNM staging of a prostate cancer can help to determine the most appropriate treatments and to predict prognosis. In this system, T represents the tumor, N represents lymph nodes, and M represents metastases, with numbers that follow these letters describing the extent of spread.

T is broken down into:

T0: With T0 tumors, there is no evidence of a tumor in the prostate gland.

T1: These tumors are often discovered "accidentally" when surgery is done on the prostate gland for another reason such as BPH or a needle biopsy for an increased PSA, and no abnormalities are noted on a digital rectal exam or imaging studies. These are broken down into:

  • T1a: The tumor is found in less than 5 percent of the prostate tissue.
  • T1b: The tumor is found in more than 5 percent of prostate tissue.
  • T1c: The tumor is found during a needle biopsy that is performed due to an increased PSA.

T2: The tumor is large enough to be felt on a rectal exam but has not spread beyond the prostate. This is broken down into:

  • T2a: The tumor is present in only one-half of 1 side of the prostate
  • T2b: The tumor involves more than one-half of 1 side of the prostate, but does not involve the other side.
  • T2c: The tumor is present on both sides of the prostate gland.

T3: The tumor has spread beyond the prostate to nearby tissues.

  • T3a: The tumor has grown beyond the prostate gland but not to the seminal vesicles.
  • T3b: The tumor has spread to the seminal vesicles.

T4: The tumor is either fixed (immobile), or has grown into tissues beyond the prostate and seminal vesicles such as into the bladder, the rectum, the pelvic wall, the levator muscles, or the muscle that controls urination (external sphincter).

N is broken down into:

  • N0: The cancer has not spread to any regional lymph nodes.
  • N1: The cancer has spread to regional lymph nodes.

M is broken down into:

  • M0: The cancer has not spread (metastasized).
  • M1: The cancer has spread (metastasized). There are three substages of M1:
  • M1a: The cancer has spread to distant lymph nodes (lymph nodes other than the nearby pelvic lymph nodes).
  • M1b: The cancer has metastasized to bones.
  • M1c: The cancer has spread to other regions of the body.

Based on these TNM values, prostate cancer is broken down into four stages. Earlier stages are slow growing, with an increased chance that the tumor will grow and spread with higher stages.

Stage I: These tumors cannot be felt on a rectal exam and involve one-half of one side of the prostate gland or less. The cells look very normal (Grade Group 1). PSA is less than 10.

Stage II: These tumors have not spread beyond the prostate gland and PSA is less than 20.

  • Stage IIA: These tumors cannot be felt and involve one-half of one side of the prostate or less.PSA is between 10 and 20. Grade Group 2.
  • Stage IIB: These tumors may or may not be felt on rectal exam. They are classified as T1 or T2. PSA is less than 20. Grade Group 2.
  • Stage IIC: These tumors may or may not be felt on exam. They are T1 or T2. PSA is less than 20, and Grade Group is 3 to 4.

Stage III: These tumors are considered locally advanced, and differ from stage II tumors in that PSA levels are high, the tumor has been growing, or the tumor is high grade (aggressive).

  • Stage IIIA: The cancer has spread beyond the prostate into nearby tissues or the seminal vesicles. PSA is 20 or higher. Grade Group 1 to 4.
  • Stage IIIB: The tumor has spread beyond the prostate into nearby tissues, and may have spread to the bladder or rectum. PSA can be any level. Grade Group 1 to 4.
  • Stage IIIC: The cancer may be within the prostate or have spread to nearby tissues (any T), but the cells appear very abnormal (Grade Group 5).

Stage IV: Stage IV prostate cancers have spread beyond the prostate.

  • Stage IVA: The cancer has spread to regional lymph nodes (N1), and may be any T, have any PSA, and be of any Grade Group.
  • Stage IVB: The cancer has spread to distant lymph nodes or other regions of the body.

Risk Groups

Prostate cancers are also broken down into risk groups. The National Comprehensive Cancer Network has combined information including the level of PSA, the size of the prostate, biopsy results, and stage, to predict the chance that a prostate cancer will grow and spread. 

  • Very low risk: These tumors are found on biopsy (T1c), but a DRE, as well as imaging tests, are normal. PSA is less than 10 ng/ml, and Gleason score is 6. Out of the core biopsy samples, the tumor was found in fewer than 3 samples, and comprised half or less of the tissue in the core sample.
  • Low risk: These tumors include those that are T1a, T1b, T1c, and T2a, have a PSA less than 10 ng/ml, and a Gleason score of 6.
  • Intermediate: Tumors that are intermediate risk have at least two of the following: They are classified as T2b or T2c, the PSA is between 10 and 20 ng/ml, and the Gleason score is 7.
  • High risk: High-risk tumors also have two or more of the following: They are classified as T3a, the PSA is greater than 20 ng, ml, and the Gleason score is between 8 and 10.
  • Very high risk: Tumors that are very high risk are classified as T3b or T4, have a group grade of 5, are present in 4 or more biopsy samples, and have a Gleason score between 8 and 10.

Follow-Up Tests/Tests for Recurrence

After the primary treatment of prostate cancer, some cancers can recur. When prostate cancer comes back it may do so locally (near the site of the original tumor) or distantly (such as in bones). Prostate cancers are more likely to recur if they have spread beyond the prostate, if they have a higher Gleason score, if they are a higher stage, and if cancer had spread to lymph nodes.

After treatment, PSA is monitored, though the frequency of testing may depend on the initial stage of the tumor as well as treatments used. If PSA is increasing, or if symptoms occur (either local symptoms, or pain in the spine, hips, or pelvis), tests to look for recurrence may include:

  • Bone scan: The most common site of distant recurrences of prostate cancer is in bones.
  • CT 
  • MRI
  • Specialized PET scans. Scans, such as Axumin PET scans and C-11 choline PET scans may be used to detect the recurrence of prostate cancer before it is found on other imaging tests.
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