How Prostate Cancer Is Diagnosed

A diagnosis of prostate cancer can involve screening tests such as a serum PSA or digital rectal exam, as well as procedures that can include 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, magnetic resonance imaging (MRI), bone scan, or PET scan may be done to stage the tumor. Since prostate cancers can differ 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 males beginning at age 50, though this is an area of active debate.

Males 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 they can help direct further testing.

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 that's secreted by prostate cells, and it 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.
  • PSA levels naturally increase with age.
  • Some people who have prostate cancer may have normal PSA tests.
  • Some medications used to treat BPH or obesity can cause reduced 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.

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.

PSA measures can 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%, a tumor is more likely to be cancer; if the result is greater than 25%, a tumor is more likely to be benign. The significance of levels between 10 and 25% is unknown.
  • PSA density: This number compares the PSA to the size of the prostate, with a higher PSA density more likely to be cancer. The test is fairly impractical, as it requires an ultrasound of the prostate.
  • Age-specific PSA: This test assesses 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)

During 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.

A DRE can be somewhat uncomfortable and may cause a sense that you need to urinate. This test is safe and it only takes a few minutes.

Tumor Markers

Tests to detect biomarkers can also be used for screening, though they are not considered routine. Biomarkers are substances that are produced either by prostate cancer or by the body when prostate cancer is present.

The 4K score and the prostate health index (PHI) can be used to determine prostate cancer risk and may help guide the need for tumor marker screening. 

Controversy and Risks

In recent years there has been considerable controversy surrounding screening since it's thought that PSA testing results in significant overdiagnosis.

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

A 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.

Have a conversation with your doctor about your recommended testing schedule in relation to your overall risk profile.

Prostate Cancer Doctor Discussion Guide

Get our printable guide for your next doctor's appointment to help you ask the right questions.

Doctor Discussion Guide Man

Tests and Procedures

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

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.

Before a transrectal ultrasound, an enema is given. During the test, 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 needed to determine if abnormal appearing regions are cancerous.

Random 12-Core Biopsy

A random 12-core biopsy may be done if a PSA is persistently abnormal, or if abnormalities are felt on a DRE or seen on TRUS. During this procedure, samples are taken from 12 random areas in the prostate gland and examined with a microscope to determine if prostate cancer cells are present.

This is usually an outpatient procedure. Practices vary, but a clear liquid diet is usually recommended for 24 hours before the test and an enema is given an hour or two before the procedure.

During the test, you would have a full bladder and you will be asked to lie on your left side. 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, and 12 to 14 samples are taken with thin, hollow needles that are placed into the prostate gland. The procedure takes roughly 20 to 30 minutes.

You may experience some rectal soreness for a few days after the procedure or have spots of blood in your stool, urine, or semen for a few days. Warm soaks and compresses may alleviate discomfort.

Multiparametric MRI (mp-MRI)

Random biopsies may miss some areas of cancer and inadvertently remove normal tissue.

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 done in advance. Targeted biopsies are limited to abnormal appearing regions.

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.

MRI Fusion Biopsy

An MRI fusion biopsy is similar to a multiparametric MRI, but it uses a combination of MRI and transrectal ultrasound (TRUS) to look for abnormal areas in the prostate. It's thought that selective biopsies will improve the accuracy of diagnosis. As with multiparametric MRI, the procedure is not available everywhere.

Prostate Cancer Gene 3 (PCA3) RNA Test

For males over age 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. Depending on the results, a repeat biopsy may be recommended. 

Staging Tests

Cancer grading is done to describe the aggressiveness of a tumor, and lab and imaging tests may be done to look for evidence of spread. Some prostate cancers are non-aggressive and would not cause a problem if left alone.

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 microscopic appearance.

A score of 3 means that the cells look well-differentiated (very much like normal prostate cancer cells); a score of 5 means that the cells appear poorly differentiated (highly abnormal).

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

Additional tests may be done to further stage the tumor.

Prostate cancer typically first metastasizes (spreads) to the tissues immediately adjacent to the prostate, including the seminal vesicles, rectum, bladder, and lymph nodes.

Prostate cancer has a 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, an alkaline phosphatase blood level may be done, 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. These tests are not usually needed for early prostate cancers or those with low Gleason scores.

Imaging 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 can be helpful to look for lymph node involvement.
  • Bone scan: Before 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. Fluciclovine F-18 (Axumin) can be used if there's concern about prostate cancer recurrence. 

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, NBN, 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 who have a family history of prostate cancer.

Stages

Prostate cancer is assigned a stage based on several factors—the cancer grade, PSA levels, and the size and metastases (spread).

TNM Staging

As with many other cancers, TNM staging of prostate cancer can help to determine the most appropriate treatments and 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 might be discovered accidentally, such as when surgery is done on the prostate gland for another reason, such as BPH, 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% of the prostate tissue.
  • T1b: The tumor is found in more than 5% 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).

Pathological Staging

With 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: Cancer has not spread to any regional lymph nodes.
  • N1: Cancer has spread to regional lymph nodes.

M is broken down into:

M0: Cancer has not spread.
M1: Cancer has metastasized.

There are three substages of M1:

  • M1a: Cancer has spread to distant lymph nodes (lymph nodes other than the nearby pelvic lymph nodes).
  • M1b: Cancer has metastasized to bones.
  • M1c: 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. 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 not 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 prostate cancer is treated, 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 and the 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 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 the 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:

Frequently Asked Questions

What does it mean if a prostate screening comes back positive?

It doesn’t mean you definitely have cancer. The test for prostate-specific antigen to identify a possible cancer has a false-positive rate of 70%. Based on the screening results, though, your doctor will redo the test or order additional tests, which may include a biopsy, to confirm the diagnosis.

What is a Gleason score?

A Gleason score is the scale used to determine whether prostate cells are cancerous and, if so, the grade or seriousness of the cancer. Two sections of cells from a biopsy are examined. Each section is graded on a scale of 1 to 5 based on how abnormal and aggressive the cells are. The scores are added together: the higher the score, the more serious the cancer.

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Article Sources
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