Biopsy and Pathology

Chapter 4: Biopsy and Pathology — Understanding Your Prostate Tissue Diagnosis

Opening Story

James, a 62-year-old retired firefighter, had been monitoring his PSA for three years. When it rose from 4.2 to 6.8 ng/mL and his MRI showed a suspicious area in the right side of his prostate, his urologist recommended a biopsy. "I was terrified," James recalls. "I didn't know what to expect — the procedure, the waiting, the results. But understanding what was happening at each step made it so much less scary. And when the pathology report came back, my doctor walked me through every line. That knowledge gave me the power to make the right decision for my life."

Part 1: Why Do You Need a Biopsy?

If your PSA is elevated, your DRE is abnormal, or your MRI shows a suspicious area, your doctor may recommend a prostate biopsy. A biopsy is the only way to definitively diagnose prostate cancer. Imaging and blood tests can raise suspicion, but only looking at actual prostate tissue under a microscope can confirm whether cancer is present and how aggressive it is.¹

It is important to understand that a biopsy samples only small pieces of the prostate — typically 12 to 14 thin needle cores — not the entire gland. This means a biopsy is like taking a few soil samples from a large garden: it gives valuable information, but it may not capture everything growing there. Studies consistently show that when the entire prostate is later removed surgically, additional cancer is often found that the biopsy missed.² This is why your doctor may recommend additional tests (MRI, biomarkers) and sometimes repeat biopsies to get the most complete picture possible.

Part 2: Types of Prostate Biopsy

There are two main approaches to performing a prostate biopsy, defined by the route the needle takes to reach the prostate:

Transrectal Biopsy (TRUS Biopsy)

This is the traditional approach, used for decades. An ultrasound probe is inserted into the rectum, and biopsy needles pass through the rectal wall into the prostate. Because the needle passes through the rectum (which contains bacteria), antibiotics are given before the procedure to prevent infection. Some centers perform a rectal swab beforehand to identify which specific antibiotics will be most effective against your particular bacteria.³

Transperineal Biopsy

In this newer approach, the biopsy needle enters through the perineum — the skin between the scrotum and the rectum. Because the needle does not pass through the rectum, the risk of serious infection (sepsis) is significantly lower. A 2026 meta-analysis of 12 studies including over 8,400 patients found that transperineal biopsy had significantly lower infection rates (risk ratio 0.68) and dramatically lower sepsis rates (risk ratio 0.16) compared to transrectal biopsy.⁴ The TRANSLATE trial (2025), the largest randomized trial comparing the two approaches (1,126 patients), also found that transperineal biopsy detected more clinically significant cancer (60% vs. 54%) and resulted in fewer hospitalizations for infection (1% vs. 2%).⁵

However, the ProBE-PC randomized trial (2024) found no significant difference in infectious or noninfectious complications between the two approaches when modern antibiotic protocols were used for transrectal biopsy.⁶ The PREVENT trial (2024) similarly found that transperineal biopsy without any antibiotics had zero infections, while transrectal biopsy with targeted antibiotic prophylaxis had a 1.4% infection rate — a difference that was not statistically significant.⁷

The NCCN guidelines note that a transperineal approach may be associated with a lower risk of sepsis and a reduced need for antibiotics compared to a transrectal approach, and both approaches remain clinically viable.⁸

When is transperineal preferred?

• If you have had a prior infection after a transrectal biopsy
• If you are at higher risk for infection (e.g., diabetes, immunosuppression)
• If the suspicious area is in the front (anterior) of the prostate, which is harder to reach transrectally
• If you have no rectum (e.g., after surgery for rectal cancer)
• If a more thorough (saturation) biopsy is needed, such as in a very large prostate or after a prior negative biopsy
• If your doctor wants to avoid antibiotics entirely (antibiotic stewardship)

When might transrectal still be appropriate?

• Patient preference or comfort
• If you cannot be positioned on your back with legs up (lithotomy position)
• Clinician training, experience, or equipment availability
• With targeted antibiotic prophylaxis (rectal swab), infection rates can be very low

Part 3: MRI-Targeted vs. Systematic Biopsy

Systematic (Template) Biopsy

Traditionally, biopsies are taken in a systematic pattern — usually 12 cores sampled from predetermined locations throughout the prostate (right and left sides; base, mid-gland, and apex; medial and lateral). This approach samples the prostate broadly but "blindly," without targeting any specific area.

MRI-Targeted Biopsy

If you had an MRI before your biopsy (which is now recommended by the NCCN as a Category 1 recommendation), your doctor can use the MRI images to target suspicious areas.⁸ This is done using MRI/ultrasound fusion technology, where the MRI images are overlaid onto the real-time ultrasound during the biopsy, allowing precise targeting of suspicious lesions.

The VISION individual patient data meta-analysis (2025) of the PRECISION and PRECISE trials (953 patients) found that MRI-targeted biopsy detected 8.7 percentage points more clinically significant cancer (36.3% vs. 27.6%) and 12.3 percentage points less clinically insignificant cancer (9.6% vs. 21.9%) compared to standard systematic biopsy.⁹ A large Cochrane systematic review confirmed these findings.¹⁰

Combined Approach (Targeted + Systematic)

Most experts recommend performing both targeted biopsies of MRI-suspicious areas and systematic biopsies during the same session. The NCCN guidelines state that most advocate for a combined targeted and systematic biopsy approach, as some high-grade cancers are uniquely detected by the systematic approach, and systematic biopsies are needed for complete risk stratification.⁸ A study from Johns Hopkins and the NIH found that combined biopsy doubled the benefit of targeted biopsy alone in detecting clinically significant cancer.¹¹

However, there is growing interest in omitting systematic biopsies in certain situations. A 2025 study found that when PSA density is ≥0.2 ng/mL/cc, the added detection of clinically significant cancer from systematic biopsy was only 2%, suggesting that targeted biopsy alone may be sufficient in these patients.¹²

Micro-Ultrasound

A newer technology, micro-ultrasound, uses very high-frequency ultrasound (29 MHz vs. standard 6–9 MHz) to visualize the prostate in much greater detail. The NCCN guidelines now note that micro-ultrasound–guided biopsy performed at expert centers was found to be non-inferior to MRI-targeted fusion biopsy for detecting clinically significant prostate cancer.⁸

Part 4: How to Prepare for a Biopsy

Your doctor will give you specific instructions, but here is a general guide:

Before the Procedure

• Medications to stop: Blood thinners (warfarin, apixaban, rivaroxaban, clopidogrel), aspirin (ask your doctor — some allow low-dose aspirin), NSAIDs (ibuprofen, naproxen), and GLP-1 receptor agonists (for diabetes/weight loss — these can delay stomach emptying if sedation is used). Always ask your doctor which medications to stop and when.
• Antibiotics: For transrectal biopsy, you will receive antibiotics before the procedure. Some centers perform a rectal swab days before to choose the most effective antibiotic. For transperineal biopsy, antibiotics may not be needed — the NORAPP trial (2022) showed that transperineal biopsy without antibiotics was non-inferior to biopsy with antibiotics for preventing infection.¹³
• Bowel preparation: For transrectal biopsy, you may be asked to use an enema the morning of the procedure to clean the rectum. This is not typically needed for transperineal biopsy.
• Eating and drinking: If the procedure is done under local anesthesia in the office, you can usually eat and drink normally. If done under sedation or general anesthesia in an operating room, you will need to fast (nothing to eat or drink) for several hours beforehand.

The Procedure Itself

For an office-based biopsy under local anesthesia (the most common setting):

1. You lie on your side with your knees bent toward your chest (for transrectal) or on your back with legs in stirrups (for transperineal)
2. An ultrasound probe (slightly larger than a thumb) is gently inserted into the rectum with lubricant
3. The doctor evaluates the prostate on ultrasound, measuring its size and looking for any abnormalities
4. If MRI fusion is being used, the MRI images are registered to the ultrasound images
5. A local anesthetic (nerve block) is injected around the prostate to numb the area
6. Biopsy needles are fired through the probe (transrectal) or through the perineal skin (transperineal), each taking a thin core of tissue about 1–2 cm long
7. Typically 12 systematic cores are taken, plus 2–4 additional targeted cores of any MRI-suspicious areas
8. Occasionally, biopsies of the seminal vesicles may be taken if there is concern about cancer spread
9. The entire procedure takes about 15–30 minutes

What the ultrasound report may describe:

• Prostate size (volume in cubic centimeters)
• Hypoechoic lesions — areas that appear darker than surrounding tissue on ultrasound. These may represent cancer but can also be caused by inflammation, atrophy, or other benign conditions
• Calcifications — bright spots that represent calcium deposits (stones) in the prostate, which are common and usually benign
• Bladder wall thickness — may indicate bladder outlet obstruction from BPH

Part 5: Side Effects of Biopsy

Most side effects are mild and temporary, but it is important to know what to expect:

Common (expected) side effects:

• Blood in urine (hematuria): Very common; may last days to weeks. Usually mild.
• Blood in semen (hematospermia): Very common; can last weeks to months. Harmless but can be alarming.
• Blood in stool (transrectal approach): Usually minor and resolves within days.
• Rectal discomfort or soreness: Mild; resolves within days.
• Perineal bruising or soreness (transperineal approach): Common; resolves within 1–2 weeks.

Less common side effects:

• Urinary difficulty or retention: About 5–6% of men may have temporary difficulty urinating or need a catheter for a short time.⁵
• Urinary tract infection: Occurs in about 1–3% of men, depending on the approach and antibiotic use.⁴
• Erectile dysfunction: Temporary changes in erections can occur but usually resolve within weeks to months.
• Fever: Low-grade fever can occur; high fever (>101°F / 38.3°C) requires immediate medical attention.

Rare but serious:

• Sepsis (bloodstream infection): This is the most feared complication. With transrectal biopsy, the historical rate was 1–3%, but with modern antibiotic protocols and the shift to transperineal biopsy, rates are now well below 1%.⁴ ⁶ ⁷
• Significant bleeding requiring intervention: Very rare.
• Hospitalization: Required in about 1–2% of cases overall.⁵

When to call your doctor or go to the emergency room:

• Fever above 101°F (38.3°C) or chills
• Inability to urinate for more than 8 hours
• Heavy bleeding that does not stop
• Severe pain
• Signs of infection (feeling very unwell, confusion, rapid heartbeat)

Part 6: Understanding Your Pathology Report

Your biopsy cores are labeled by location and sent to a pathologist — a doctor who specializes in examining tissue under a microscope. The pathology report is one of the most important documents in your cancer journey. Here is how to understand it:

The Gleason Grading System

The Gleason system, developed in the 1960s and refined multiple times since, describes how the cancer cells are arranged — essentially, how much they still look like normal prostate glands.¹⁴

Normal prostate glands have a well-organized structure. Cancer disrupts this organization. The pathologist assigns a Gleason pattern number (3, 4, or 5) based on how abnormal the glands appear:

• Pattern 3: Individual, well-formed glands that are recognizable but abnormal. This is the least aggressive pattern.
• Pattern 4: Poorly formed, fused, or cribriform (sieve-like) glands. The normal gland structure is breaking down. This is more aggressive.
• Pattern 5: No recognizable gland formation at all — sheets of cells, single cells, or areas of dead tissue (necrosis). This is the most aggressive pattern.

Patterns 1 and 2 are no longer used in modern grading.¹⁴

The Gleason Score

The Gleason score is the sum of the two most prominent patterns seen in your biopsy:

• First number = the most common (predominant) pattern
• Second number = the second most common or highest pattern

For example: Gleason 3+4 = 7 means mostly pattern 3 (well-formed glands) with some pattern 4 (poorly formed glands).

This distinction matters enormously: Gleason 3+4 = 7 has a significantly better prognosis than Gleason 4+3 = 7, even though both add up to 7.¹⁴ ¹⁵

The Grade Group System

Because the Gleason system can be confusing (the lowest score assigned today is 6 out of 10, which sounds like a failing grade), the International Society of Urological Pathology (ISUP) introduced a simpler Grade Group system in 2014, now adopted by the World Health Organization:¹⁴

Survival data from Johns Hopkins radical prostatectomy database.¹⁵

Why Grade Group 1 (Gleason 6) May Not Be "Cancer"

There is a growing movement among experts to reclassify Grade Group 1 prostate cancer. When a patient hears "You have cancer, Gleason 6 out of 10," it sounds frightening — as if they are already halfway to the worst possible score. In reality, Gleason 6 is the lowest grade assigned today, and these tumors have an extremely low risk of spreading or causing harm. Many experts believe that calling it "cancer" leads to unnecessary anxiety and overtreatment.¹⁴ ¹⁶ This is why active surveillance (monitoring without immediate treatment) is the preferred approach for most men with Grade Group 1 disease (see Chapter 8).

Part 7: What Else to Look for on Your Pathology Report

Beyond the Gleason score and Grade Group, your pathology report contains several other important pieces of information:

Number and Percentage of Positive Cores

Your report will state how many of the biopsy cores contain cancer (e.g., "4 of 12 cores positive" or "33% cores positive"). More positive cores generally indicate a larger tumor volume. This information helps determine your risk category and treatment options.

Length and Percentage of Cancer in Each Core

For each positive core, the report states how much of the core is involved by cancer (e.g., "6 mm of cancer in a 15 mm core" or "40% involvement"). Greater involvement suggests more extensive disease.

Targeted Core Results

If MRI-targeted biopsies were taken, these are reported separately from the systematic cores. The targeted cores often show the highest-grade cancer because they sample the most suspicious area seen on MRI.

Perineural Invasion (PNI)

PNI means cancer cells are seen growing along or around nerves within the prostate. This is a well-established adverse prognostic factor on biopsy, associated with a higher risk of cancer extending beyond the prostate capsule.¹⁷ However, PNI alone does not change your Grade Group or necessarily change your treatment — it is one piece of the puzzle your doctor considers.

Intraductal Carcinoma of the Prostate (IDC-P)

IDC-P is a specific pattern where cancer cells grow within the existing ducts and glands of the prostate, rather than invading through them. It is recognized by the World Health Organization as a distinct entity and is strongly associated with aggressive, high-grade cancer.¹⁸ ¹⁹

Key points about IDC-P:

• Its presence on biopsy strongly suggests high-grade cancer is present, even if the invasive cancer seen is lower grade
• IDC-P is considered a contraindication to active surveillance by 95% of genitourinary pathology experts surveyed²⁰
• The NCCN guidelines state that IDC without invasive carcinoma should be managed as cancer (referred to the prostate cancer treatment guidelines), with strong consideration for repeat biopsy using MRI guidance⁸
• IDC-P is associated with higher rates of lymph node metastasis, biochemical recurrence, and resistance to systemic therapy¹⁹ ²¹

Atypical Intraductal Proliferation ([AIP](/rare-disease/acute-intermittent-porphyria))

AIP is a "gray zone" lesion — more atypical than high-grade PIN but not quite meeting the strict criteria for IDC-P. When found on biopsy without invasive cancer, AIP is associated with a 50% risk of finding invasive carcinoma or IDC on repeat biopsy. The NCCN recommends repeat biopsy using MRI targeting and systematic biopsy.⁸ ²²

High-Grade Prostatic Intraepithelial Neoplasia (HGPIN)

HGPIN is a precancerous condition — abnormal cells that line the prostate glands but have not invaded through the gland walls. HGPIN alone, especially if found in only one or two cores, does not significantly increase the risk of finding cancer on repeat biopsy and does not require immediate repeat biopsy. However, if HGPIN is extensive (many cores) or if other risk factors are present (rising PSA, abnormal MRI), your doctor may recommend further evaluation.⁸

Low-Grade Prostatic Intraepithelial Neoplasia (LGPIN)

LGPIN is considered a normal finding and has no clinical significance. It does not increase your risk of prostate cancer and requires no follow-up.

Atypia / Atypical Small Acinar Proliferation (ASAP)

"Atypia, suspicious for cancer" or ASAP means the pathologist sees cells that look abnormal but cannot definitively call them cancer — perhaps because the suspicious area is too small or the tissue was damaged during processing. This finding carries a significant risk (about 40–50%) of finding cancer on repeat biopsy, and the NCCN recommends repeat biopsy in 12–24 months with increased sampling of the atypical site.⁸

Cribriform Architecture

Cribriform glands are a specific subtype of Gleason pattern 4 where cancer cells form a sieve-like (perforated) pattern. Large cribriform architecture is associated with particularly aggressive behavior and is considered an unfavorable histologic feature. The NCCN specifically states that active surveillance is not recommended for patients with favorable intermediate-risk disease and unfavorable histology such as expansile/large cribriform histology or intraductal carcinoma.²³

Part 8: The Value of a Second Pathology Opinion

Prostate cancer grading is inherently subjective — different pathologists looking at the same tissue may assign different Gleason scores. This is not a failure of pathology; it reflects the genuine difficulty of interpreting complex tissue patterns under a microscope.

How often do opinions differ?

• A 2022 study found that secondary pathology review changed the total Gleason score in 29% of cases (19% downgraded, 10% upgraded), and changed the NCCN risk group in 19% of patients²⁴
• A study of second opinions at an academic center found a 27% disagreement rate on prostate biopsies, with 7.6% of cases having changes that would alter treatment candidacy (e.g., from active surveillance to definitive treatment or vice versa)²⁵
• A Johns Hopkins study found that pathology review changed the Gleason score by at least 1 point in 44% of cases, and changed the risk category in about 10% of men²⁶
• A 2026 telepathology concordance study of 11 expert urologic pathologists found only fair agreement (weighted kappa 0.34) among experts, with the most common disagreement being Grade Group 1 vs. Grade Group 2²⁷

The most common area of disagreement is the boundary between Grade Group 1 (Gleason 6) and Grade Group 2 (Gleason 3+4=7) — precisely the boundary that determines whether a patient is a candidate for active surveillance or should consider definitive treatment.²⁵ ²⁷

Should you get a second opinion?

Many experts recommend having your biopsy slides reviewed by a genitourinary subspecialty pathologist (a pathologist who specializes in urologic cancers), especially:

• If you are considering active surveillance (confirming Grade Group 1 is critical)
• If the grade is borderline (e.g., Gleason 6 vs. 7, or 3+4 vs. 4+3)
• If the findings seem inconsistent with your other test results
• Before any major treatment decision

Major academic centers such as Johns Hopkins, UCSF, MD Anderson, and others offer pathology review services. Your doctor can arrange for your slides to be sent for review. Insurance typically covers second opinions.

Part 9: Biopsy-to-Surgery Grade Changes

It is also important to understand that even with a perfect biopsy interpretation, the grade found at biopsy may differ from the grade found when the entire prostate is removed surgically (radical prostatectomy). This is because the biopsy samples only a small fraction of the prostate.

A 2026 SEER analysis of nearly 60,000 men found:²⁸

• Overall concordance between biopsy and surgical Gleason score: 70%
• Among biopsy Gleason 6 (Grade Group 1): 67% were upgraded at surgery (mostly to Grade Group 2)
• Among biopsy Gleason 7: 90.5% concordance (the most reliable)
• Among biopsy Gleason 8: 57.5% were downgraded at surgery

An earlier large SEER study of over 34,000 men found overall concordance of 55%, with a weighted kappa of 0.51 (moderate agreement).²⁹ Pre-biopsy MRI has been shown to improve concordance and reduce upgrading rates.³⁰

These numbers are not meant to alarm you — they simply reflect the reality that a biopsy is a sampling procedure. This is why your doctor considers the biopsy results alongside your PSA, MRI findings, biomarker results, and clinical examination to build the most complete picture of your cancer.

Questions to Ask Your Doctor

1. Will my biopsy be transrectal or transperineal? Why?
2. Will MRI-targeted biopsies be included, or only systematic biopsies?
3. How many cores will be taken?
4. What antibiotics will I receive, and do I need a rectal swab first?
5. Which medications should I stop before the biopsy, and when can I restart them?
6. Will the biopsy be done in the office under local anesthesia or in the operating room?
7. When will I get my results, and who will explain them to me?
8. What is my Gleason score and Grade Group?
9. How many cores are positive, and what percentage of each core is involved?
10. Is there perineural invasion, intraductal carcinoma, or cribriform architecture?
11. Should my slides be sent for a second pathology opinion?
12. What does my pathology report mean for my treatment options?

Myth vs. Fact

• Myth: "A prostate biopsy is extremely painful."

Fact: Most men describe the biopsy as uncomfortable but tolerable, especially with a good local nerve block. The PREVENT trial found that on a 0–10 pain scale, the average pain score was low for both approaches, though transperineal biopsy may cause slightly more immediate discomfort that resolves quickly.⁷ Many men say the anticipation was worse than the actual procedure.

• Myth: "If my biopsy is negative, I definitely don't have cancer."

Fact: A negative biopsy reduces the likelihood of cancer but does not eliminate it. The NCCN guidelines state that a negative prostate biopsy does not preclude a diagnosis of prostate cancer on subsequent biopsy.⁸ If your PSA continues to rise or your MRI is suspicious, your doctor may recommend repeat biopsy or additional testing.

• Myth: "Gleason 6 is a dangerous cancer that needs immediate treatment."

Fact: Grade Group 1 (Gleason 6) has an extremely low risk of spreading or causing death. Many experts believe it should be reclassified as a non-cancerous condition. Active surveillance is the preferred management for most men with this diagnosis.¹⁴ ²³

• Myth: "A biopsy can spread the cancer."

Fact: There is no credible evidence that a prostate biopsy causes cancer to spread. This is a common fear but is not supported by medical science. The biopsy needle is too small to displace cancer cells in a clinically meaningful way.

• Myth: "All pathologists will give the same Gleason score."

Fact: Gleason grading has significant interobserver variability. Studies show disagreement rates of 27–44% between pathologists.²⁴ ²⁵ ²⁶ This is why second opinions from subspecialty pathologists are valuable, especially for borderline cases.

Key Takeaways

1. A prostate biopsy is the only way to definitively diagnose prostate cancer. It involves taking small tissue samples from the prostate using needles guided by ultrasound, with or without MRI fusion targeting.
2. Two approaches exist: transrectal (through the rectum) and transperineal (through the perineum). Transperineal biopsy has lower infection and sepsis rates and may detect slightly more clinically significant cancer, but both approaches are safe and effective.
3. MRI before biopsy is now a Category 1 recommendation by the NCCN. MRI-targeted biopsy finds more clinically significant cancer and less insignificant cancer than systematic biopsy alone. Most experts recommend combining both approaches.
4. The Gleason score and Grade Group system describe how aggressive your cancer appears under the microscope. Grade Group 1 (Gleason 6) is the least aggressive and is often managed with active surveillance. Grade Group 5 (Gleason 9–10) is the most aggressive.
5. Your pathology report contains critical information beyond the Gleason score: number of positive cores, percentage of involvement, perineural invasion, intraductal carcinoma, and cribriform architecture all influence your treatment plan.
6. Second pathology opinions are valuable — Gleason scores change in 27–44% of cases on expert review, and about 10–19% of men are reclassified into a different risk group. This can change treatment recommendations.

Support Resources

• Prostate Cancer Foundation: pcf.org — Understanding your pathology report
• ZERO — The End of Prostate Cancer: zerocancer.org — Patient education and support
• American Cancer Society: cancer.org — Prostate cancer biopsy information
• NCCN Patient Guidelines: nccn.org/patients — Free patient-friendly guidelines
• Us TOO International: ustoo.org — Peer support and education
• Johns Hopkins Pathology: For second opinion pathology review services
• Epstein Grading System Resources: Educational materials on the Grade Group system

References

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