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To Biopsy or Not to Biopsy: Managing a Negative Prostate Magnetic Resonance Imaging Scan

By: Benjamin T. Ristau, MD, MHA | Posted on: 01 Sep 2022

Multiparametric MRI is an evidenced-based tool for the evaluation, diagnosis, and management of prostate cancer.1 Contemporary MRI results are reported via a Likert2 or Prostate Imaging–Reporting and Data System® (PI-RADS®)3 score ranging from 1 through 5. A “negative” MRI is defined as a Likert or PI-RADS score of 1–2.4,5

Two large, multicenter trials provide a good estimate of how often a urologist will encounter a negative MRI. PROMIS recruited 576 biopsy-naïve men (mean±SD age 63.7±7.6 years; PSA 7.1±2.9 ng/ml).4 All men received MRI interpreted by dedicated urological radiologists. The incidence of negative MRI was 27%. PRECISION randomized 500 men to standard 10–12 core transrectal biopsy (248 patients, mean±SD age 64.5±8 years; PSA 6.5 ng/ml, IQR 5.1–8.6) or MRI-guided prostate biopsy (252, 64.4±7.5 years; PSA 6.75 ng/ml, IQR 5.1–9.3).5 Men with normal MRIs in the MRI-guided prostate biopsy group were not biopsied. The incidence of a negative MRI was 28%. Therefore, urologists can expect to see a negative MRI 25%–30% of the time.

Urologists and patients are concerned about missed cancer diagnosis if biopsies are omitted in the setting of a negative MRI. Given the indolent nature of low-grade prostate cancers,6 most urologists care about missed diagnoses of clinically significant disease (≥Grade Group 2).

The negative predictive value (NPV) of MRI can be defined as the likelihood that a negative MRI truly characterizes the absence of clinically significant prostate cancer. The best controlled study to consider NPV of MRI was the PROMIS trial.4 In PROMIS, all patients had an MRI and underwent combined template mapping biopsy (core biopsies every 5 mm), followed by 10–12 core transrectal prostate biopsy. Detection of clinically significant prostate cancer was defined as ≥Grade Group 3 or ≥6 mm maximum cancer core length of any grade in any location. A secondary definition including all cancers ≥Grade Group 2 or ≥4 mm maximum cancer core length of any grade in any location was also considered. The NPV of MRI was 89% (95% CI 83%–94%) according to the primary definition and 72% (95% CI 65%–79%) based on the secondary definition.

Two meta-analyses have considered the NPV of MRI. Moldovan and colleagues assessed NPV of MRI in 9,613 patients across 43 studies.7 Clinically significant prostate cancer was defined as Gleason Score ≥7. The median NPV for clinically significant prostate cancer was 88.1% (IQR 85.7%–92.3%). Sathianathen et al included 42 studies (7,321 patients) to determine the NPV of MRI of clinically significant prostate cancer in biopsy-naïve men.8 The definition of clinically significant prostate cancer was defined in 2 ways: 1) ≥Grade Group 2 and 2) ≥Grade Group 3. The NPV was 90.8% (95% CI 80.1%–92.4%) for definition 1 and 97.1% (95% CI 94.9%–98.7%) for definition 2.

Table. Retrospective institutional studies examining NPV of MRI

Study No. Pt Population Yrs Age (IQR) PSA (IQR) MRI NPV (%)
Wysock et al9 75 BN: 29
PNB: 25
AS: 21		 62 (57–68) 4.7 (3–6.5) All: 98.7
BN: 100
PNB: 96
AS: 100
Lu et al10 100 BN: 38
PNB: 33
AS: 29		 65 (59–69) 5.5 (4.3–9.4) All: 97
BN: 97.4
PNB: 100
AS: 93.1
Yerram et al11 125 Not specified 60 (36–81) 7.11 (0.3–64.7) 92
Boesen et al12 194 PNB: 161
AS: 33		 63 (58–67) 11 (7.9–17) 95
Itatani et al13 193 BN Not reported Not reported 89.6
Panebianco et al14 1,255 BN: 659
PNB: 596		 BN: 66 (62–69)
PNB: 68 (60–72)		 BN: 5.9 (3.9–7.6)
PNB: 5.6 (3.2–7.8)		 BN: 95
PNB: 96
AS, active surveillance. BN, biopsy naïve. PNB, prior negative biopsy.

Other retrospective studies have pegged the NPV of MRI for clinically significant prostate cancer at 89.6%–100% (see Table),9–14 depending on the characteristics of the population being studied. Taken together, the overall risk of missing a clinically significant prostate cancer when biopsy is omitted in the face of a negative MRI lies somewhere between 0% and 12%.

“Urologists and patients are concerned about missed cancer diagnosis if biopsies are omitted in the setting of a negative MRI.”

To better calibrate downside risk, it is important to consider what is being missed when biopsy is omitted in men with a negative prostate MRI. Recall that in PROMIS, Ahmed and colleagues reported a negative MRI in 27% patients.4 Of these, 10.7% had clinically significant cancers based on their primary definition. All these cancers were Grade Group 2, ranging from 6 to 12 mm. No Grade Group 3–5 tumors went undetected by MRI.15 An et al considered 114 men who underwent prostate biopsy within 1 year of a negative prostate MRI.16 In this cohort, the distribution of biopsy results was 77.2% no cancer, 19.3% Grade Group 1, and Grade Group 2 or higher in 3.6%. In a subset of 20 biopsy-naïve patients, none had clinically significant cancers when biopsy was performed following a negative MRI.

If missing up to 12% of favorable intermediate- or low-grade prostate cancers is unacceptable to patients or clinicians, there are 2 factors that can be considered together with MRI results: 1) PSA density and 2) individual cancer risk stratification.

Low PSA density is associated with improved NPV in the setting of a negative MRI. Oishi and colleagues examined 135 men with a negative pre-biopsy MRI.17 The NPV of MRI was 82% in all comers, but this improved to 90% in men with a negative MRI and PSA density <0.15 ng/ml/cc. Washino et al performed a similar analysis in 170 patients with MRI designated as PI-RADS ≤3.18 Of 44 patients with PI-RADS ≤3 and PSA density <0.15 ng/ml/cc, none had ≥Grade Group 2 cancers diagnosed. Finally, Venderink and colleagues demonstrated an NPV of 94% in ruling out ≥Grade Group 2 disease for men with PSA density <0.15 ng/ml/cc and MRIs with PI-RADS ≤3 lesions.19 Low PSA density (<0.15 ng/ml/cc) combined with a negative MRI increases confidence that a negative MRI result is a true-negative.

Individual cancer risk stratification based on clinical parameters (ie prevalence of disease) is another powerful tool to improve NPV of MRI. An illustration is helpful to understand the impact of disease prevalence on the NPV of a test (see Figure).

Figure. Calculation of NPV of MRI when prostate cancer incidence in the study population is 10% (A) versus 30% (B).

Let’s assume MRI sensitivity of 91% and specificity of 37% for the detection of clinically significant prostate cancer.20 Consider what happens when we vary the prevalence of clinically significant prostate cancer from 10% (part A of Figure) to 30% (part B of Figure) in the population. When the prevalence of clinically significant prostate cancer is 10%, NPV of MRI is 97%. However, when the prevalence increases to 30%, the NPV drops to 90%. While the NPV of MRI may vary across institutions,21 the principle that greater disease prevalence in a population lowers NPV remains consistent. One solution for the variance of MRI test characteristics across institutions is to perform quality assurance analysis on the population at your own institution. In this way, test performance (sensitivity, specificity, NPV) can be calculated locally and applied accurately.

“The decision on whether to perform a biopsy in men with a negative MRI can be challenging. However, risk can be objectively calibrated using readily available clinical information.”

Once local NPV is known, there are multiple ways to estimate individual risk of prostate cancer. The Prostate Biopsy Collaborative Group produced a model using clinical parameters with an output of risk of high-grade prostate cancer (≥Grade Group 2).22 An online calculator can be found at http://riskcalc.org:3838/PBCG/. The ERSPC (European Randomized Study of Screening for Prostate Cancer) Rotterdam data also provided a risk calculator with an output of ≥Grade Group 2 or clinical stage >T2b. An online calculator can be found at https://www.prostatecancer-riskcalculator.com/seven-prostate-cancer-risk-calculators. Either of these tools can be used to estimate individual prostate cancer risk and applied to known MRI test performance characteristics. Potential downsides of omitting biopsy with a negative MRI can be quantified and communicated to patients in a shared decision-making model.

The decision on whether to perform a biopsy in men with a negative MRI can be challenging. However, risk can be objectively calibrated using readily available clinical information. This risk stratification can then be communicated to patients and shared decisions can be made incorporating individual risk tolerance.

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