Prostate Biopsy & Grading of Tumours

Prostate biopsy is performed either for diagnosis of prostate cancer when it is suspected or for confirmation when cancer is present.

The majority of men undergoing prostate biopsy do so when the potential benefits of an early diagnosis outweigh the risks of biopsy. See Benefits of Prostate Biopsy below.

Confirmation of cancer and assessment of histology (including genetic testing) is helpful when a diagnosis of prostate cancer has been made based on other clinical criteria (e.g. very high PSA, bone scan or physical exam).

The benefits of prostate biopsy include:

1. Early diagnosis if cancer is present. In select circumstance, early diagnosis and treatment leads to reduced risk of cancer-related disability and death.

2. Reassurance. When cancer is suspected but not found there may be a substantial reduction in distress. While a negative biopsy does not completely exclude the presence of cancer (see below) it does substantially reduce the possibility that cancer is present.

3. Access to care. Some types of therapies for prostate cancer (e.g. systemic therapy for advanced cancer or clinical trials) require a histologic diagnosis of cancer.

The risk of prostate biopsy come in 2 forms:

1. Overdiagnosis leading to over treatment. These are the same considerations that apply to prostate cancer in general.

2. Risks associated directly with the biopsy including discomfort, bleeding, infection and urinary retention. Read below.

Prostate biopsy may be declined by the patient at any time during the diagnostic process.

There is currently no alternative to biopsy to confirm a diagnosis for cancer. Therefore, patients who decline biopsy may continue with screening for prostate cancer (the form of which is determined via a shared decision making model) or to forego prostate cancer screening altogther.

Ultrasound is used to sample the prostate through ‘sextants’ - the gland is split in RIGHT and LEFT sides and each side is split into an apex, mid gland and base for a total of 6 areas. 1-2 samples are drawn from each area resulting in a total of 10-12 cores are obtained. A thorough sampling is obtained through the most common areas that prostate cancer may occur.

Sometimes called ‘registration’ biopsies. Areas of interest that have been identified on MRI are specifically sampled. The targeting may be done by importing the MRI image data into an ultrasound platform (‘image fusion’) or with the radiologist reviewing the images on MRI and using their minds eye to sample the areas of interest (‘cognitive fusion’). Multiple samples are taken from the area(s) of interest.

This is when a systematic/template biopsy is combined with a targeted/fusion biopsy. Usually, the targeted cores are taken first then an additional 8-10 samples evenly spread through the remainder of the gland are taken. This has the highest diagnostic yield but is more likely to find ‘insignificant’ cancers and there is s slightly higher risk of a complication because there are more samples taken.

Scheduling of biopsies is arranged by the hospital. Wait times for imaged fused biopsy may be several months. Call the office if you have not heard from the hospital for a time for your biopsy (1) within 2 months for a template biopsy or (2) within 6 months for a template + targeted biopsy or (3) at the direction of your urologist (we may specify when you should call if you have not heard anything). Once you have the date, you can complete the rest of the process.

Your prostate biopsy may occur at one of several hospitals determined by availability and/or special needs (e.g. fusion or sedation)

Go to Life Labs for any blood work (e.g. INR/PTT) that was recommended prior to biopsy. Go no sooner than 2 months prior to but no later than 2 weeks prior to the date of your biopsy.

Biopsies are done on an outpatient basis in the radiology department. The biopsy takes between 20-40 minutes. You can expect to be in hospital for 2-3 hours.

Clear fluid is OK but don’t eat anything else. If you are scheduled for a biopsy with sedation, nothing to eat or drink from midnight prior to the biopsy though you may take your medications with sips of clear fluid the morning of the biopsy.

Please follow the instructions on the prescription provided.

You will be prescribed an antibiotic at the time a decision is made to have the biopsy, either on paper or we will usually send the prescription directly to the pharmacy. Pick it up at your pharmacy well before the date of the biopsy.

Take the antibiotic(s) on the morning of the biopsy PRIOR to going to the hospital.

Fleet enema can be purchased over the counter at your pharmacy (no prescription is needed). Follow the instructions on the bottle. The benefit of this is controversial but it remains a recommendation because there is no associated harm to the intervention.

Blood thinners include all of the following:

Antiplatelet medications must be stopped 7 days prior to biopsy. Antiplatelets include aspirin (ASA), ibuprofen (Advil, Motrin), Celebrex, Naprosyn, Ticlid, Plavix (Clopidogrel), ticagrelor (Brilinta), prasugrel (Effient).

Anticoagulants: Warfarin/Coumadin should be stopped 5 days prior to biopsy with measurement of INR the day prior to the biopsy. E.g., if the biopsy is on a Friday, last dose of Coumadin on Saturday leaving 5 full days (Sunday through Thursday) off the medication.

Anticoagulants: apixaban, dabigatrn, rivaroxaban, edoxaban, and similar should be stopped 2 full days prior to the biopsy. E.g., if the biopsy is on a Friday, last dose of medication on Tuesday with no medication Wednesday, Thursday or Friday.

Natural blood thinners such as vitamin E, fish oils and ginger should be stopped 7 days prior to biopsy.

Resume your blood thinner as directed by your urologist. In most cases, you may resume your blood thinner once there is no more visible blood in the urine and stool - usually a few days.

Choice of antibiotic will be determined by your urologist and individualized to your circumstances (including past history of infections, current risk of multi-drug resistant bacteria, safety profile of antibiotics, guideline recommendations, antibiotic stewardship programs) . Current guideline recommendations (EAU 2021, AUA 2020 and CUA 2015):

One full day of antibiotics. This may be a single dose of long-acting antibiotic or 2 separate doses. 3-day regimens are no longer considered a standard of care.

1. Fluoroqinolone (e.g. Cipro XL 1000 mg) SINGLE DOSE . Considered an acceptable regimen based on AUA and CUA recommendations. The European Commission has recommended against fluoroquinolones for antibiotic prophylaxis.

2. Augmented antibiotics: the use of 2 different classes of antibiotics (e.g. a fluoroquinolone plus fosfomycin).

3. Targeted antibiotics based on rectal/peri-rectal swab culture and sensitivities.

Alternative schedules.

1. Fosfomycin 3 grams prior and an additional dose 24-48 hours after biopsy.

2. Ceftriaxone 1 grams im at time of biopsy.

3. Gentamicin 3 mg/kg iv at time of biopsy.

4. Cefixime (Suprax) 400 mg daily x 3 days starting 1 day prior to biopsy.

5. As advised by infectious diseases.

Lightner et al. Best practice statement on urologic procedures and antimicrobial prophylaxis. Journal of Urology 2020.

Mottet et al. EAU Prostate Cancer Guidelines 2021. On Line: uroweb.org/duideline/prostate-cancer/#5

Mrkobrada et al. CUA guidelines on antibiotic prophylaxis for urologic procedures. Canadian Urological Association Journal 2015.

Pilatz et al. Antibiotic prophylaxis for the prevention of infectious complications following prostate biopsy: a systematic review and meta-analysis. Journal of Urology 2020.

It is normal to see blood in the urine, stool and ejaculate. Virtually everyone has this.

This usually lasts for a few days, but may last for several weeks and may be intermittent. The blood may be bright red or dark/rusty brown.

Heavy bleeding from the rectum is rare. If you have heavy bleeding, proceed to the nearest Emergency.

This is the most serious complication after biopsy.

Between 1 in 30 and 1 in 100 men will have an infection despite antibiotic prophylaxis. Augmented antibiotic protocols have an infectious risk of less than 1%.

Symptoms include a flu-like illness with fever, fatigue and difficulty urinating. Typically occurs within the first few days after the biopsy. Infection may spread from the prostate to the blood stream, bladder, epididymis or testis. 1 in 3 men who have an infection require admission to hospital and the remainder are treated on an outpatient basis. While severe infections are rare, they can be life threatening and some men who require admission for treatment may require admission to the intensive care unit.

Go to Emergency if you have symptoms of infection. They will start a broad spectrum antibiotic such as MEROPENEM until the results of the cultures are back. Most men will require 2-4 weks of antibiotics to clear the infection

Swelling of the prostate gland may occlude the urethra and you may be unable to urinate. This is an uncommon complication occurring in less than 1% of patients but is more common in men with pre-exisiting obstruction or large prostate glands. Go to the emergency department if you are unable to urinate.

If you are fortunate enough to have a ‘negative’ prostate biopsy this means that there was no cancer in the sampled prostate tissue. By extrapolation it is unlikely that the unsampled tissue harbors cancer. An important caveat is that no currently available test which can exclude the presence of prostate cancer with 100% certainty because of the inherent limitations of prostate biopsy and imaging. It should be of some reassurance that while there is always a risk of a false negative biopsy (this is an inherent property of any sampling approach, including biopsy) the risk of death following a negative biopsy is low.

A population-based review of the Danish Prostate Cancer Registry showed that the future risk of prostate cancer mortality was quite low in men who had a negative biopsy (Klemann et al, Lancet Oncology 2017). The 15 year risk of prostate cancer specific mortality with benign initial biopsy stratified by initial PSA at the time of the biopsy was the following:

PSA <10 mcg/L: 0.7%

PSA 10-20% mcg/L: 3.6%

PSA >20 mcg/L: 17.6%

The ERSPC randomized clinical study reported an 11 year cancer-specific mortality of 0.03% after a negative prostate biopsy (Schroder Eur Urol 2010). There are a number of explanations for the differences in mortality but the outcomes in the ERSPC data are more likely to reflect the results of current screening and diagnostic strategies.

Men who present with an elevated initial risk, those with longer life-expectancies and those in whom the screening characteristics change unfavorably require special attention. The decision to proceed with a second round biopsy should account for the characteristics of the first biopsy (prostate size, number of cores) and the patient's present risk assessment and life expectancy. The current guideline recommendation is to proceed with an MRI prior to a second biopsy in the majority of cases.

In order to mitigate the risks of a falsely negative biopsy a patient should have a PSA and DRE at an appropriate interval, often yearly.

Atypical small acinar proliferation (ASAP) is a pathologists way of saying “there might be cancer there but I’m not certain enough to make the call, consider re-biopsy”.

The risk recorded in the literature for cancer following the diagnosis of atypical glands suspicious for carcinoma on needle biopsy is 30-40%, which is twofold compared to that following a benign diagnosis. Clinical parameters do not help in stratifying which men with atypical glands are at increased risk of being diagnosed with cancer. Approximately 80% of the subsequently diagnosed cancers are Grade Group 1 (Gleason score 6), with the remaining cases of higher grade, including 5% with Grade Groups 4-5 (Gleason scores 8-10). Therefore, approximately 90% of patients will have no cancer or inconsequential cancer on repeat biopsy, however, 10% of patients will have clinically significant cancer on subsequent biopsy and overall 2% will have very high grade cancers.

Consequently, for cases with atypical glands on biopsy, follow-up is warranted with serum or urine tests, imaging, and, in select cases, repeat biopsy with relatively increased sampling of the atypical gland sites

HGPIN is when there is a proliferation of abnormal epithelial cells but these are confined to the prostatic acini - they do not breach the barrier of the basement membrane which is necessary to make a diagnosis of cancer.

The risk recorded in the literature for cancer following the diagnosis of HGPIN needle biopsy is 20-30%, which is not much higher than the risk reported in the literature for a repeat biopsy following a benign diagnosis. The majority of publications which have examined the risk of cancer following a needle diagnosis of HGPIN to the risk of cancer following a benign diagnosis on needle biopsy have shown no differences between the 2 groups. Clinical parameters do not help in stratifying which men with HGPIN are at increased risk of being diagnosed with cancer. It is recommended that men with a single core showing HGPIN do not need a routine repeat needle biopsy. If multiple cores show HGPIN on biopsy, the risk of subsequent cancer risk is twofold compared to that following a benign diagnosis. However, most subsequently detected cancers are Grade Group 1 (Gleason score 6) and would simply be observed. Therefore, approximately 96% of men will either have no cancer or inconsequential cancer on repeat biopsy. The risk of a high grade cancer Grade Group 2 or higher (Gleason score 7) on subsequent biopsy is approximately 4%.

Consequently, for cases with multifocal HGPIN, follow-up is warranted with serum or urine tests, imaging, and, in select cases, repeat biopsy with relatively increased sampling at the HGPIN sites. It is important to note that the vast majority of the literature was prior to the widespread use of screening MRI. In those patients in whom MRI was part of the screening process, the risk of a missed cancer is likely to be even lower than that quoted above.

A false-negative biopsy is when a cancer is present but not detected during the test. Basically, the needle misses the tumor. A false-negative biopsy may be detected in hindsight (patient has a subsequent biopsy in which cancer is found) or because a diagnosis of cancer has been established on a prior biopsy.

False-negative biopsies are an inherent property and limitation of any type of biopsy, including prostate biopsy, since biopsy are only samples. They are generally not the result of medical error or incompetence.

Biopsies are evaluated by a specially trained physician (a pathologist) with a microscope, sometimes using special techniques to define the different structures in the sample or to do genetic testing. The pathologist reports their findings based on the tissue that was sampled.

There is no currently available test that can exclude the presence of prostate cancer with 100% certainty.

Tumor grade is the most important factor. It is derived from the appearance and pattern of cancerous cells under a microscope. Most closely correlates with tumor behavior: risk that the tumor will (or has) spread outside the prostate and risk of local growth. See below for more detail.

More is generally worse but not as important as the grade. Volume of tumor can be quantified in several ways.

1. Number of cores which have cancer.

2. Percent of cores having cancer .

3. Amount of tumor present within each core: either a percent or absolute length of core involved (e.g. mm or %).

Other tumor features that help refine some part of the risk of the tumor.

Perineural invasion (PNI): cancer is seen around the small nerves within the prostate. Cancer may uses these conduits as a path to spread outside of the prostate capsule. PNI can increase the chances that extraprostatic extension (EPE) will be found at the time of surgery. It can guide the surgical approach but does not exclude surgery or radiation as treatment options.

Lymphovascular invasion (LVI): this is almost exclusively seen in the highest grade/risk tumors. Usually goes hand in hand with Gleason 8 or higher tumors (Grade Group 4/5 and 5/5). This is a poor prognostic factor and associated with a higher risk of disease spread to the lymph nodes and outside the capsule. Rarely affects management choice, but the risk of relapse is always higher - as it is for patients with high-grade tumors.

Invasive cribriform carcinoma (ICC): typically only seen in high risk disease; increased the aggressiveness of tumor above and beyond that defined in the grade whenever ICC is present.

Intraductal carcinoma (IDC): typically only seen in high risk disease; increased the aggressiveness of tumor above and beyond that defined in the grade whenever IDC is present.

Primary grade is the 'most common pattern in the specimen'. This is determined 'geographically'. As an analogy, earth has 2 common surface features - water and land. The most 'common' feature is water. Similarly, the most common pattern, regardless of its grade, is assigned the 'Primary Grade'.

Secondary grade in a biopsy is currently the highest grade. This was not always the case - it used to be the second most common geographic pattern. It has been recognized that the highest grade predicts tumor behavior better than the second most common pattern.

Lastly, THE LOWEST GRADE WHICH CAN CURRENTLY BE ASSIGNED IS A 3/5 (THREE OUT OF FIVE). In the past, the lower grade was a 1/5 (one out of five). It has since been appreciated that Gleason 1/5 and 2/5 do NOT behave in any sort of cancerous manner despite the fact that the appearance is different from normal prostate tissue. As a results, the lowest grade and score combination is the following:

Primary Grade 3/5 + Secondary Grade 3/5 = Gleason Score 6/10

In the past, Gleason 1/5 tumors were still read by the Pathologist as cancer and therefore Gleason Score 2/10-5/10 tumors were possible. This is no longer the case - and no patient is every assigned a Gleason Score of less than 6/10 in the current era. For obvious reasons, this has created a great amount of confusion amongst patients and non-urologists. Intuition tells us that the closer the number is to the maximum of 10, the worst the tumor must be. This is, in fact, the opposite. Low grade tumors rarely cause problems as the overall picture is usually one of low risk (though there are always exceptions) and these are often managed with an Active Surveillance approach. Here is a sampling the current Gleason Grades and possible Gleason Scores

There is no risk that a prostate biopsy will seed cancer along the biopsy site or cause it to spread through the body. Some types of cancer other than prostate cancer can be seeded into the blood or surrounding tissue but this does not appear to be the case with prostate cancer. Multiple studies have demonstrated that prostate cancer does not behave in this way.

See the discussion above. If cancer is found in the sample, then the prostate definitely contains cancer. If no cancer is found in the sample, then the prostate is unlikely to contain cancer. Sometimes the results of a biopsy are indeterminant and additional testing is required. See the discussion on false-negative prostate biopsy above.

No (not yet). Obtaining a sample of prostate tissue, either by biopsy or transurethral resection, is the only definitive way to diagnose prostate cancer. There are rare circumstances where a presumptive diagnosis of prostate cancer is made based on clinical evaluation and where the risks of a biopsy are not justified given the clinical picture. There are promising investigational approaches (e.g. liquid biopsy and genetic tests) but these have not been proven in clinical practice.