The Highest Grade Group Does Not Drive the Risk of Recurrence when Systematic and Multiparametric Magnetic Resonance Imaging (MRI)-targeted Biopsies are Discordant: Preliminary Findings Using Radical Prostatectomy Pathology as a Surrogate for MRI-targeted Biopsy Grade

Abstract

Pathology grading of prostate biopsy follows the rule that the highest International Society of Urological Pathology grade group (GG) is the GG assigned. This rule was developed in the systematic biopsy (SBx) era and makes sense when samples are from very different areas of the prostate. This rule has been kept for multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy (MRI-TBx), for which multiple samples—targeted and systematic—are taken from small areas. In particular, if the results for SBx and MRI-TBx are discordant, the patient is assigned the higher GG. However, the most appropriate grading when MRI-TBx and SBx grades are discordant has never been investigated empirically. A cohort of patients who have undergone SBx and MRI-TBx with long oncological follow-up does not yet exist. To estimate the risk of recurrence for every combination of biopsy and pathological grades, we used the GG on radical prostatectomy (RP) as a surrogate for GG on MRI-TBx GG surrogate. We analyzed data for 12 468 men who underwent SBx and RP at a tertiary referral center and assessed 5-yr biochemical recurrence–free survival (bRFS) for each pairwise combination of biopsy and surgical GG results. We found that for cases with discordant SBx and RP grades, the risk of recurrence was intermediate, irrespective of whether the highest grade was at RP or SBx. For instance, the 5-yr bRFS rate was 57% for men with GG 3 on RP and 60% for men with GG 3 on SBx, but 63% for men with RP GG 3 and SBx GG 2, and 79% for men with RP GG 2 and SBx GG 3. Translating these findings to MRI-TBx casts doubt on current grading practice: when GGs are discordant between SBx and MRI-TBx, the risk of biochemical recurrence risk is not driven by the highest grade but by an intermediate between the two grades. Our findings should motivate studies assessing long-term outcomes for patients undergoing both MRI-TBx and SBx with a view to empirically evaluating current grading practices.

Patient summary:

Patients with prostate cancer may undergo two biopsy types: (1) systematic biopsy, for which sampling follows a systematic template; and (2) targeted biopsy, for which samples are taken from lesions detected on scans. There may be a difference in prostate cancer grade identified by the two approaches. In such cases, the risk of cancer recurrence seems to be predicted by an intermediate grade between the lower and higher grades.

Routine use of multiparametric magnetic resonance imaging (mpMRI) before prostate biopsy is recommended by international guidelines [1,2] on the grounds that mpMRI increases the rate of detection of International Society of Urological Pathology grade group (GG) ≥2 prostate cancer while reducing both unnecessary biopsies and overdiagnosis of GG 1 cancer. Before the introduction of mpMRI, when systematic biopsy (SBx) of the prostate was the standard of care, pathologists adopted the rule of assigning an overall grade according to the highest grade for any core. This makes sense because if, for instance, a core from the right lateral peripheral zone was GG 4, the patient would require treatment irrespective of whether a core from the left anterolateral peripheral zone was benign, GG 1, GG 2, or GG 3. This rule was retained after the introduction of mpMRI, in our view, without full consideration of the implications [3]. In fact, the most appropriate grade when mpMRI-targeted biopsy (MRI-TBx) and SBx present discordant GG results has never been empirically investigated. The most efficient way to evaluate the appropriate grading approach would be to take a large group of patients who have undergone both MRI-TBx and SBx and been followed for many years for oncological outcomes. However, as mpMRI is a relatively recent technology, follow-up is limited. It is known that MRI-TBx grade reflects the pathology grade for radical prostatectomy (RP) relatively well [4], and hence the best alternative would be to use the RP pathology grade as a surrogate for MRI-TBx grade. This would allow us to look at a large cohort of patients who have been followed for a long time. In this study, we attempted to estimate the risk of biochemical recurrence (BCR) for every combination of biopsy and pathology grade to gain insight into the relative oncological risk for tumors detected via MRI-TBx and SBx.

We analyzed a retrospective cohort of 12 468 consecutive patients who received a diagnosis of prostate cancer after SBx alone and then underwent RP between 1999 and 2022 at a tertiary referral center. The cohort included both men who underwent SBx at our center and men whose biopsies were performed externally and internally reread by a dedicated uropathologist. In approximately half of the cases, only the specimens with the highest GG were provided and reviewed, resulting in a total of 6546 men for whom ≥12 cores were read by the pathologist. We used Kaplan-Meier methods to estimate 5-yr BCR-free survival (bRFS) for each pairwise combination of SBx and RP GG results. A sensitivity analysis was performed to assess oncological outcomes for the patients who had at least 12 cores evaluated by our specialist uropathologist. We combined GG 4 and GG 5 owing to the limited number of patients in these two groups.

Overall, 2593 men experienced BCR and 3951 followed for at least 5 yr had no evidence of recurrence. The clinical and pathological characteristics of this cohort are shown in Table 1. Table 2 shows 5-yr bRFS estimates according to pairwise combinations of the highest GG at SBx and the highest GG at RP. There is a relatively high proportion of patients with low GG who underwent RP as the study period starts before the widespread adoption of active surveillance: in contemporary practice, active surveillance rather than radical prostatectomy is recommended for patients with GG 1 cancer.

Table 1 –

Clinical and pathological characteristics of the 12 468 patients who underwent systematic prostate biopsy and then radical prostatectomy

Variable	Result
Median age at surgery, yr (IQR)	61 (56–66)
Clinical stage, n (%)
cT1	6892 (55)
cT2	4703 (38)
cT3–4	873 (7.0)
Median PSA at surgery, ng/ml (IQR)	6 (4–8)
Median number of cores taken, n (IQR)	12 (6–13)
Median number of positive cores, n (IQR)	3 (2–6)
Extraprostatic extension, n (%)	8053 (65)
Seminal vesicle invasion, n (%)	1179 (9.5)
Lymph node invasion, n (%)
pN0	10 190 (82)
pN1	1188 (9.5)
pNx	1090 (8.7)
Positive surgical margin, n (%)	2287 (18)
Biochemical recurrence (n)	2593

IQR = interquartile range; PSA = prostate-specific antigen.

Table 2 –

5-yr bRFS rate according to the highest grade group at SBx and the highest grade group at RP for the overall population (N = 12 468)

SBx GG	5-yr bRFS, % (95% CI)
	Grade group at radical prostatectomy				SBx GG
	GG 1	GG 2	GG 3	GG 4–5
	(n = 2451)	(n = 6262)	(n = 2400)	(n = 1355)
GG 1	[n = 2069]	[n = 1865]	[n = 186]	[n = 34]	94 (93–95)
(n = 4154)	97 (96–98)	93 (92–95)	78 (71–85)	61 (46–82)
GG 2	[n = 352]	[n = 3535]	[n = 700]	[n = 71]	82 (80–83)
(n = 4658)	96 (93–98)	85 (83–86)	63 (58–67)	47 (36–61)
GG 3	[n = 26] a	[n = 674]	[n = 951]	[n = 223]	60 (57–63)
(n = 1874)	96 (89–100)	79 (75–83)	52 (49–56)	32 (26–40)
GG 4–5	[n = 4] a	[n = 188]	[n = 563]	[n = 1027]	42 (39–45)
(n = 1782)	100 (100–100)	80 (73–88)	52 (47–57)	30 (27–33)
RP GG	97 (96–98)	87 (86–88)	57 (55–60)	32 (29–35)

bRFS = biochemical recurrence-free survival; SBx = systematic biopsy; RP = radical prostatectomy; GG = International Society of Urological Pathology grade group; CI = confidence interval.

^aLow number of events with unreliable estimate.

As expected, the probability of recurrence increased with GG. However, of particular interest, where SBx and RP pathology grades differed, the risk of recurrence was intermediate, irrespective of whether the highest grade was for RP pathology or SBx. For example, the 5-yr bRFS rate was 57% for men with GG 3 at RP and 60% for men with GG 3 on SBx, but 63% for men with GG 3 at RP and GG 2 on SBx, and 79% for men with GG 2 at RP and GG 3 on SBx. A sensitivity analysis of patients with ≥12 biopsy specimens read by the uropathologist confirmed this finding, showing that the number of biopsies does not affect our main outcome (Supplementary Table 1).

Our findings are supported by previous research showing dramatically better oncological outcomes for patients with high grade on RP pathology who had low risk according to biopsy [5,6]. Here, we generalize this finding to show that risk is always lower than the highest grade when grades are discordant, irrespective of risk group. We can translate these results into the setting of men who undergo SBx and MRI-TBx. In clinical practice, if SBx and MRI-TBx results are discordant, the patient is typically assigned the higher of the two grades. Our findings cast doubt on this practice: the risk is not as great as the risk for the higher grade, it is intermediate. There are several possible mechanisms for our findings. First, discordant grades suggest that the higher-grade lesion may be of relatively lower volume. Alternatively, GG 2, GG 3, and GG 4 critically depend on the ratio of Gleason pattern 3 to 4; discordant grades suggest the possibility of misestimation of this ratio, in particular because of a lower volume of Gleason pattern 4.

Given that we used RP pathology as a surrogate for MRI-TBx results, our findings should be seen as preliminary and a motivation for further research using long-term data for patients undergoing both MRI-TBx and SBx. It is possible that our initial findings will not hold because of the additional information provided by imaging. Moreover, a very large cohort will be needed to obtain accurate estimates for rare combinations, such as patients with GG 4–5 on SBx but low grade on MRI-TBx. Nonetheless, the results of such a study could have important implications for how we grade, and consequently how we treat, prostate cancer.