Pathological Assessment of Men with Grade Group 2 Prostate Cancer

Accurate grading at the time of diagnosis is fundamental to risk stratification and treatment decision making for men with localized prostate cancer. Active surveillance has become a widely used strategy for men with small volume, low-grade disease [1]. There are several published guidelines for active surveillance eligibility ranging from strict to liberal criteria. In 2019 the National Comprehensive Cancer Network (NCCN) guidelines expanded their inclusion criteria for active surveillance to include men with ‘favorable intermediate-risk’ prostate cancer (Grade Group [GG] 2, <50% positive cores, prostate-specific antigen [PSA] <10 ng/mL, and clinical stage ≤T2a) [2]. In addition to this, American Urological Association (AUA) and Dutch Urological Association (DUA) support careful selection of patients with GG2, PSA >20 ng/mL and clinical stage T3 disease [3]. There has been ongoing debate for this treatment option in this cohort of men due to concerns of misclassification and poorer long-term outcomes [4]. GG upgrading has been associated with several adverse outcomes including extraprostatic extension (EPE), positive surgical margins and seminal vesical invasion (SVI), which are predictive of subsequent biochemical recurrence [5]. A greater understanding of identifying men with GG upgrading and adverse outcomes is essential to guide patients towards appropriate treatment options and improve oncological outcomes.

Our study aims to determine the association of clinicopathological variables and strategies to identify men with GG2 prostate cancer at risk of upgrading and having adverse pathological features.

This retrospective study includes 243 patients with GG2 prostate cancer that were consecutively treated with radical prostatectomy between 2015 and 2021. Patients who were on active surveillance, previous history of prostate biopsy and/or received hormonal and/or radiation therapy prior to surgery were excluded from this study. A retrospective analysis was conducted using clinicopathological data obtained from medical records.

The standard of care for men being evaluated for prostate cancer was to undergo a multiparametric magnetic resonance imaging (mpMRI) scan prior to biopsy using a transperineal approach. Target and systematic prostate biopsies were performed for men who had a positive result on mpMRI that is, in whom an area with a Prostate Imaging Reporting and Data System (PI-RADS) score of 3, 4, or 5 was identified. In men who did not have an mpMRI a systematic biopsy was performed. Radical prostatectomy was performed by a single high-volume surgeon during the study period. Prostate biopsy and prostatectomy specimen were assessed by experienced genitourinary pathologists. The Intuitional Research Ethics Committee approved this study protocol (ETH00789). The requirement to obtain informed consent was waived.

The primary outcome was to determine risk factors for GG upgrading on radical prostatectomy specimen. GG upgrading was defined as the presence of GG3–5. Clinically useful cut-off points were used for risk stratification, determined by various thresholds of PSA level, mpMRI findings and prostate biopsy characteristics. PSA subgroups were categorized into the following risk groups, PSA <10 ng/mL, PSA 10–15 ng/mL, and PSA >15 ng/mL. Similarly, percentage of high grade (Gleason pattern 4) on prostate biopsy was categorized as <5%, 5%–10%, and >10%. Total length of GG2 on biopsy (mm) were categorized as greater than or less than 10 mm.

Secondary outcome was to determine risk factors for ‘composite poor outcomes’, defined as the presence of GG3–5 or EPE or SVI or lymphovascular invasion (LVI) or lymph node (LN) involvement on prostatectomy specimen. Strategies using various combinations of PSA level, mpMRI findings and prostate biopsy characteristics were formulated to identify men at highest risk of upgrading and having composite poor outcomes.

Chi-squared tests were used to determine associations between primary and secondary outcomes and PSA, MRI and biopsy variables. Different strategies for identifying patients with 1) upgrading and 2) composite poor outcomes were determined using multivariant analyses. Statistical significance was declared when computed p values were <0.05. Analyses were performed using Stata Version 17 (Stata Co.).

Patient characteristics are displayed in Table 1. Among the 243 men with GG2 prostate cancer, the median age and median preoperative PSA were 64 years (interquartile range [IQR] 59–69 years) and 5 ng/mL (IQR 3.6–7.1 ng/mL) respectively. A positive digital rectal examination was seen in 127 (52.26%) of men. Overall, 152 men underwent a mpMRI for prostate cancer. Among these men, 58 (38.16%) had a PI-RADS 5 lesion and 94 (61.84%) had PI-RADS <5 lesion. Median number of positive cores obtained were 5 (IQR 3–8) and median total length of GG2 on biopsy was 9.5 mm (IQR 4–22 mm). The median percentage of high grade (Gleason pattern 4) on prostate biopsy was 10% (IQR 5%–20%).

Table 1
Clinical and pathological characteristics (total n=243)

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There were 202 (83.13%) men who had no upgrading and 41 (16.87%) men had upgrading (GG3–5) on final prostatectomy specimen (Table 2). PSA and PI-RADS score were statistically significant variables for association with upgrading. In men with PSA <10 ng/mL, PSA 10–15 ng/mL, and PSA >15 ng/mL, 33 (15.07%), 4 (22.22%), and 4 (66.67%) men upgraded in each PSA subgroup respectively (p=0.008). Additionally, 10 (10.64%) men with PI-RADS lesion <5 and 15 (25.86%) men with PI-RADS 5 lesion upgraded on prostatectomy (p=0.014).

Table 2
Comparison of prostate-specific antigen (PSA), MRI, and biopsy variables with Grade Group (GG) upgrading and composite poor outcomes on prostatectomy

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Overall, there were 113 (46.5%) men with the presence of composite poor outcomes. PSA, PI-RADS score, presence of EPE or SVI on MRI, number of positive cores on prostate biopsy, percentage of high grade (Gleason pattern 4) on prostate biopsy and total length of GG2 on biopsy (mm) were all statistically significant variables (Table 3). Higher PSA levels was associated with a greater percentage of men who had presence of composite poor outcomes (p=0.013). In men with PI-RADS 5 lesion, 41 (70.69%) men had presence of composite poor outcomes (p<0.001). Similarly, SVI and EPE on MRI were statistically significant variables with 3 (100%) and 26 (83.87%) men respectively, having presence of composite poor outcomes. Men who had <3, 3–5, and >5 positive cores on biopsy respectively had 10 (22.73%), 36 (39.13%), and 67 (62.62%) men with the presence of composite poor outcomes (p<0.001). Furthermore 71 (59.66%) men with total length of GG2 on biopsy ≥10 mm had presence of composite poor outcomes (p<0.001).

Table 3
Strategies for identifying upgrading and composite poor outcomes in men with Grade Group 2 prostate cancer

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Strategies were created using preoperative clinical and pathological variables to determine the association of men with GG2 prostate cancer at risk of 1) upgrading or 2) harboring composite poor outcomes. In strategy 1, men with PSA >10 ng/mL or PI-RADS 5 lesion, 72 men met the strategy criteria. From this group, 19 (26.39%) upgraded and 53 (73.61%) did not upgrade (p=0.010) (Table 3). Furthermore, strategy 2, 3, 7, 9, and 10 were all statistically significant in determining risk of upgrading. For men with composite poor outcomes, the above strategies were also found to be significantly associated with this outcome (Table 3).

In particular, strategy 8 (PI-RADS 5 lesion or percentage high grade [Gleason pattern 4] on prostate biopsy grade >10% or >3 cores positive on prostate biopsy) had significant association to composite poor outcomes. Using this strategy, 201 men met the criteria from which 106 of 113 men were identified with composite poor outcomes (p<0.001).

Accurate risk stratification plays a pivotal role in guiding treatment management for prostate cancer patients. Large scale studies have demonstrated that patients with GG upgrading were significantly associated with biochemical recurrence, distant metastasis and death from prostate cancer [6, 7]. Therefore, it is vital to identify risk factors associated with 1) upgrading and 2) composite poor outcomes to avoid under-treatment, especially among those who are considered appropriate candidates for active surveillance.

In our study, we evaluated the association of clinicopathological variables with upgrading outcomes of men diagnosed with GG2 prostate cancer. Overall, there was 41 (16.87%) men who upgraded (GG3–5) from initial biopsy findings. The rates of upgrading for men with GG2 disease are variable in the reported literature, ranging between 20% and 30% [8, 9]. The discordance between biopsy grading and prostatectomy grading may be accounted for by sampling error or variations in pathological reporting [10].

The use of prebiopsy mpMRI and MRI targeted biopsies has transformed diagnosis and treatment of prostate cancer. Several studies have demonstrated that the use of prebiopsy mpMRI decreases the rate of upgrading in prostatectomy [11, 12]. Alqahtani et al [8] reported upgrading rates in men with GG2 disease on prostate biopsy who had prebiopsy MRI, were similar to the present study (30/175, 17.1%). While there have been studies evaluating risk factors for predicting upgrading in men with prostate cancer [13, 14, 15, 16, 17], they are often limited by their inclusion criteria of men with low volume, favorable risk GG2 disease. A recent publication explored the risk of upgrading in men with GG2 prostate cancer without cribriform or intraductal pattern, and found age, clinical stage T3, percentage Gleason pattern 4 and presence of PI-RADS 5 lesions as independent predictors for upgrading in this cohort of men [18].

In our analysis we identified PSA level and PI-RADs score as significant predictors for upgrading on prostatectomy. Of the 6 men who had PSA >15 ng/mL, 4 (66.67%) were found to have upgraded on prostatectomy (p=0.008). Similarly, 15 (25.86%) men with PI-RADS 5 lesion upgraded on prostatectomy (p=0.014). Another key finding in our paper was determining which strategies were associated with upgrading on prostatectomy. Using strategy 3 and strategy 8 identified the largest number of men who upgraded with 36/41 (87.8%) men and 37 (18.41%) of men respectively. Using these strategy, the least number of men would be missed who upgraded on final prostatectomy. Furthermore, using strategies 9 and 10 (Table 3) maximized the number of men that upgraded that met the criteria, 13 (39.39%) and 12 (37.5%), respectively (p<0.001). These strategies allow for a more comprehensive approach in determining the risk of upgrading in men with GG2 prostate cancer in comparison to established nomograms [19].

Another key outcome in our study was determining the association of clinicopathological features with the presence of composite poor outcomes. The presence of upgrading or EPE, or SVI or LVI or LN involvement have been well described in the literature as being unfavorable prognostic characteristics [20, 21, 22]. Overall, there were 113 (46.5%) men with the presence of composite poor outcomes. PSA level, PI-RADS score, presence of EPE or SVI on MRI, number of positive cores, percentage of high grade (Gleason pattern 4) on prostate biopsy and total length of GG2 on biopsy (mm) were all statistically significant variables associated with composite poor outcomes. All men with PSA >15 ng/mL and presence of SVI on mpMRI were found to have composite poor outcomes. Similarly men with PI-RADS 5, the presence of EPE on MRI, >5 positive cores on prostate biopsy and ≥10 mm total length of GG2 on biopsy were significantly associated with a large percentage of men having composite poor outcomes, 41 (70.69%), 26 (83.87%), 67 (62.62%), and 71 (59.66%) respectively.

In addition to this, we identified strategy 8 (PI-RADS 5 lesion or high grade [Gleason pattern 4] >10% or >3 cores positive on biopsy) as the most effective strategy to minimize the number of men with composite poor outcomes being missed. Using this strategy, 106/113 (93.8%) of men with composite poor outcomes were able to be identified. Strategy 6 (PSA >10 ng/mL and PI-RADS score 5 and >3 positive cores and high grade [Gleason pattern 4] >10%) was the strictest strategy with 5 men meeting the criteria of which 4 (80%) had the presence of poor composite outcomes. This is a small sample and further studies are needed to validate these strategies.

Our study has certain limitations. The data on men with GG2 prostate cancer was retrospectively collected at a single institution which may have resulted in a selection bias. During this period, it was the routine for the authors to recommend active treatment in men with GG2 prostate cancer. Not all men underwent an mpMRI due to financial cost or due to contraindications to an mpMRI. Information on the biopsy technique was not evaluated which may have confounding impact on the detection of prostate cancer. Furthermore, radiological features such as location of the tumor was beyond the scope of this study, however this may be an important consideration for predictors of upgrading and poor outcomes to help improve our strategies.

Overall, our results show that the risk of upgrading and composite poor outcomes among men with GG2 prostate cancer can be up to 16.87% and 46.5%, respectively. The results from this study highlight detailed clinical and biopsy information which can better predict men at risk of harboring adverse pathology. Our study strongly favors the use of strategy 8 (PI-RADS 5 lesion or high grade [Gleason pattern 4] >10% or >3 cores positive on biopsy) as the most effective strategy to minimize the number of men with upgrading and composite poor outcomes being missed. The use of our strategies may improve treatment decision making for clinicians when considering men for active surveillance.

Our study allows a further understanding of clinicopathological features associated with upgrading and composite poor outcomes for men with GG2 prostate cancer on biopsy. We believe our strategies have the potential to improve treatment decision making by more accurately identifying patients at risk of having adverse pathology at radical prostatectomy. Further validation of the use of these strategies is warranted.