How Prostate Cancer Is Diagnosed

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. 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.

prostate cancer diagnosis
Illustration by Verywell

Screening Tests

The vast majority of prostate cancers are discovered on screening tests before any signs and symptoms occur. The two main screening tests are the prostate-specific antigen (PSA) test and digital rectal exam, which are best when used together; neither of these tests should be used alone.

In general, screening is recommended for men beginning at age 50, though this is an area of active debate. Men who have risk factors for prostate cancer, such as a family history of the disease, are usually advised 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.

Prostate Specific Antigen (PSA) Testing

The PSA test is a simple blood test that determines the level of prostate-specific antigen 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 naturally 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 cutoff of 4 nanograms per milliliter (ng/ml) 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 this value suggests cancer. It's not known how helpful this test is at the current time.
  • Free PSA: Free PSA is the percentage of PSA in the blood that is not bound to proteins. If the result is less than 10 percent, the tumor is more likely to be cancer; if the result is greater than 25 percent, the tumor is more likely to be benign. Unfortunately, many levels will fall between 10 percent 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. 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 versus 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 with this approach. While the procedure can be somewhat uncomfortable and may cause a sensation of needing to urinate, it's very important to use this test along with the PSA.

    Tumor Markers

    Tests to detect biomarkers can also be used for screening, though they are not considered routine. Biomarkers are substances that are either produced by a prostate cancer itself or by the body when a prostate cancer is present. Two of these tests include the 4K score and the prostate health index (PHI); tests that can be used to predict which men may develop prostate cancer or high-risk prostate cancer. 

    Controversy and Risks

    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 follow-up tests (targeted or random biopsies) and treatments can pose significant risks, such as hospitalization and urinary or sexual side effects, respectively.

    Have an open conversation with your doctor about this and your own testing schedule in relation to your overall risk profile.

    Tests and Procedures

    If a screening test (PSA and/or DRE) is abnormal, further testing with diagnostic tests may be needed to determine if a prostate cancer is actually present and, if so, the aggressiveness of the cancer. Options include:

    Transrectal Ultrasound (TRUS)

    A transrectal ultrasound (TRUS) may be used to help identify abnormalities. This approach may be used alone to calculate PSA density or combined with MRI to determine areas that should be biopsied. In a transrectal ultrasound, an enema is given and a thin, lubricated ultrasound probe is inserted into the rectum. Sound waves are delivered to the prostate (which lies directly in front of the rectum) and a picture of the prostate gland is generated. Discomfort is usually mild and consists of a feeling of fullness in the rectum. 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

    A random 12-core biopsy may be done if a PSA is persistently abnormal, or abnormalities are felt on a DRE or seen on TRUS. 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. Practices vary, but men are often placed on a clear liquid diet for 24 hours before the test and given an enema an hour or two before the procedure. While lying on their left side with a full bladder, the area of the rectum where the biopsies will be done is numbed locally with lidocaine. 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.

    Men may experience some rectal soreness for a few days after the procedure. Some men also 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.

    Multiparametric MRI (mp-MRI)

    Since random biopsies may miss some areas of cancer and inadvertently remove 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 the random 12-core biopsy, but an MRI is first done to define any suspicious regions. Biopsies are then limited to these abnormal appearing regions, what's known as a targeted biopsy.

    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 healthcare professional training.

    MRI Fusion Biopsy

    An MRI fusion biopsy is similar to the multiparametric MRI, but it uses a combination of MRI and transrectal ultrasound (TRUS) to look for abnormal areas in the prostate. Similarly, it's thought that selective biopsies are done based on the information obtained this way will improve the accuracy of diagnosis. As with multiparametric MRI, the procedure is not available everywhere and requires specialized professional training.

    Prostate Cancer Gene 3 (PCA3) RNA Test

    In men over 50, if a PSA is persistently elevated but a biopsy does not reveal cancer, the genetic test gene 3 (PCA3) RNA may be recommended. This test measures the ratio of PCA3 RNA to PSA RNA in the urine. 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. Gleason score grading is done to describe the aggressiveness of a tumor, and lab and imaging tests may be done to look for any evidence of spread.

    Gleason Score Grading

    To determine the Gleason score, the prostate cancer cells in two different areas of the tumor are each given a grade between 3 and 5 based on their appearance under the microscope. A score of 3 means that the cells look very much like normal prostate cancer cells (well-differentiated); a score of 5 means that the cells appear highly abnormal (poorly differentiated).

    The two scores in the two biopsies are combined to determine the final Gleason score:

    • Gleason 6: A score of 6 defines 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.

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

    • Grade group 1: Gleason 6 tumors
    • Grade group 2: Gleason 7 tumors (3 + 4 = 7). These are made up of primarily well-formed glands.
    • Grade group 3: Includes another type of Gleason 7 tumors (4 + 3 = 7). These, are primarily made up of poorly-formed glands.
    • Grade group 4: Gleason 8 tumors
    • Grade group 5: Gleason 9 and Gleason 10 tumors

    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

    In addition to PSA levels that are included with staging, and alkaline phosphatase blood level may be done along with imaging tests as this blood test may be elevated if bone metastases are present.

    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 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 to 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 classical positron emission tomography (PET scan) 18-F-fluorodeoxyglucose (FDG) is of limited utility in the management of prostate cancer, as the uptake of FDG in prostate cancer is highly variable. Early studies suggest that 18-fluorine-labeled choline, 18-F sodium fluoride, fluciclovine F-18, and 11-carbon-labeled acetate may be better tracers for use in recurrent prostate cancer. Currently, the use of these tracers is considered investigational. 

    Gene Testing

    Recently, gene tests have begun to play a role in determining the aggressiveness of some prostate cancers. Examples of mutations associated with both an increased risk of developing prostate cancer, as well as a greater likelihood that a diagnosed prostate cancer will be aggressive include BRCA2 gene mutations, mutations in BRCA1, ATM, CHEK2, NBD, and more. There are a number of panels available that test for several of these mutations, including Oncotype Dx, ProstaVysion, Prolaris, Test, and Decipher.

    At the current time, gene testing is often done for those with a family history of prostate cancer or for those who are treated at one of the larger research-oriented cancer centers, but it's likely these tests will become commonplace in both the diagnosis and staging of the disease in the future.

    Stages 

    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.

    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.

    Clinical TNM Staging

    In clinical staging, 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 one side of the prostate.
    • T2b: The tumor involves more than one-half of one 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, rectum, pelvic wall, pelvic (levator) muscles, or the muscle that controls urination (external sphincter).

    In pathological staging, T is broken down into:

    T2: The tumor is only in the prostate.

    T3: The tumor extends beyond the prostate

    • T3a: The tumor involves the neck of the bladder.
    • T3b: The tumor extends into the seminal vesicles.

    T4: The tumor is fixed (immobile), or is growing into regions other than the seminal vesicles such as the rectum, bladder, pelvic wall, or levator muscles.

    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 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 that have been updated by the American Joint Committee on Cancer. 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 half of one side of the prostate gland or less. In a case when a radical prostatetomy is performed, the cancer is confined to prostate. 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 half of one side of the prostate or less. In a case when a radical prostatetomy is performed, the cancer is confined to the prostate. PSA is between 10 and 20. Grade group is 1.
    • 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 is 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 is 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 is 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.
    prostate cancer: stage at diagnosis
    Illustration by Verywell 

    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 are either classified as T2b or T2c, OR the PSA is between 10 and 20 ng/ml, OR the Gleason score is 7.
    • High risk: Tumors that are high-risk are either classified as T3a, OR the PSA is greater than 20 ng/ml, OR the Gleason score is 8 to 10.
    • Very high risk: Tumors that are very high risk are classified as T3b or T4, OR have a primary Gleason score of 5, OR four or more biopsy samples have a Gleason score of 8 to 10/grade group 4 or 5.

    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. There are three ways in which PSA levels after treatment may predict the prognosis of the disease:

    • PSA doubling time: The more rapidly the PSA doubles, the greater the likelihood that the cancer will spread and become difficult to treat.
    • PSA nadir: After treatment, the absolute lowest level to which PSA falls is referred to as the PSA nadir. This number can describe both the success of treatment and the risk of recurrence. In general, a PSA nadir of 0.5 ng/ml or greater is associated with a greater risk of recurrence.
    • Relapse interval: The more quickly that PSA begins to rise after treatment, the poorer the prognosis in general.

    If PSA is increasing or if symptoms occur, tests to look for recurrence may include:

    • Bone scan: The most common site of distant recurrences of prostate cancer is bone.
    • CT 
    • MRI
    • Axumin or C-11 choline PET scans, which may be used to detect the recurrence of prostate cancer before it is found on other imaging tests.

    Differential Diagnoses

    All of this information will be useful to you if you have a positive screening test or are formally diagnosed with prostate cancer and need to better understand your disease. However, it's important to know that a number of other conditions can cause similar symptoms.

    While some of these conditions are easily distinguished from prostate cancer, others pose more of a challenge. Advances in magnetic resonance imaging (MRI) have greatly improved the ability to discriminate between prostate cancer and some conditions that were previously hard to tell apart.

    Conditions and causes that need to be considered in the differential diagnosis of prostate cancer include:

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