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Prostate cancer upgrading or downgrading of biopsy Gleason scores at radical prostatectomy: prediction of “regression to the mean” using routine clinical features with correlating biochemical relapse rates

Recommendations for managing clinically localized prostate cancer are structured around clinical risk criteria, with prostate biopsy (PB) Gleason score (GS) being the most important factor. Biopsy to radical prostatectomy (RP) specimen upgrading/downgrading is well described, and is often the rationale for costly imaging or genomic studies. We present simple, no-cost analyses of clinical parameters to predict which GS 6 and GS 8 patients will change to GS 7 at prostatectomy. From May 2006 to December 2012, 1590 patients underwent robot-assisted radical prostatectomy (RARP). After exclusions, we identified a GS 6 cohort of 374 patients and a GS 8 cohort of 91 patients. During this era, >1000 additional patients were enrolled in an active surveillance (AS) program. For GS 6, 265 (70.9%) of 374 patients were upgraded, and the cohort included 183 (48.9%) patients eligible for AS by the Prostate Cancer Research International Active Surveillance Study (PRIAS) standards, of which 57.9% were upgraded. PB features that predicted a >90% chance of upgrading included ≥7 cores positive, maximum foci length ≥8 mm in any core, and total tumor involvement ≥30%. For GS 8, downgrading occurred in 46 (50.5%), which was significantly higher for single core versus multiple cores (80.4% vs 19.6%, P = 0.011). Biochemical recurrence (BCR) occurred in 3.4% of GS 6 upgraded versus 0% nonupgraded, and in GS 8, 19.6% downgraded versus 42.2% nondowngraded. In counseling men with clinically localized prostate cancer, the odds of GS change should be presented, and certain men with high-volume GS 6 or low-volume GS 8 can be counseled with GS 7-based recommendations.

to December 2012, 1590 patients underwent robot-assisted radical prostatectomy (RARP). In this same era, >1000 additional patients were enrolled in an AS program. Key inclusion criteria were for two cohorts: biopsy GS (3+3) undergoing RARP (n = 396) and biopsy GS (4+4) undergoing RARP (n = 145). Exclusion criteria included neoadjuvant hormones or chemotherapy (n = 67), diagnosed with transurethral prostate resection (n = 9), or biopsy Gleason pattern 5. After exclusions, 374 patients in the GS (3+3) cohort and 91 patients in the GS (4+4) were eligible for final analysis. All outside biopsies were re-reviewed by a small core of genitourinary pathologists, and all RP specimens were read by a single experienced genitourinary pathologist (ISUP 2005 criteria 8 ). Data abstraction included demographics, patient and disease characteristics, and the Prostate Cancer Research International Active Surveillance Study (PRIAS) Active Surveillance criteria (T1c-T2, PSA ≤10 ng ml −1 , one or two positive cores, prostate-specific antigen density [PSAD] <0.2 ng ml −1 ). 9 We noted biopsy features such as high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP) status. We measured all possible ratios of biopsy core and tumor foci metrics, i.e., number of positive cores, percent of positive cores, maximum positive core length, percent of max positive core length in the core, total positive core length, and percentage of PCa in the specimen (total length of the positive core/total core length). In addition, associated presence of GS 6-7 score was evaluated in GS (4+4) patients (as opposed to all cores GS [4+4]). Postoperative evaluation included GS changes, pathological stage, and biochemical recurrence (BCR). Patients with a PSA level >0.2 ng ml −1 were considered as BCR after RARP during the follow-up period.
Of note, this cohort is predominately in the perfusion biopsy era, and most patients would have had only 10-12 core systematic biopsies performed in or out of the institution, with all cases having outside pathology re-reviewed.

Statistical analyses
Statistical analysis was performed using STATA/SE version 14.1 statistical software (Stata Corp., LP, College Station, TX, USA). Descriptive statistics were used to summarize the study population. Student's t-test (or Wilcoxon's rank sum) and Person's Chi-square test (or Fisher's exact test) were used to find association between groups. Univariate logistic regression methods and receiver operating characteristics (ROC) were used to determine the best cutoff points for continuous variables. Kaplan-Meier methods were used to determine BCR-free survival rates in each group. Statistical significance was considered as P < 0.05.
BCR occurred in 9 (2.4%) patients in a median (interquartile range [IQR]) follow-up of 63 (46-82) months. All of these cases were in the upgraded group. There was no difference between the upgraded and nonupgraded patients in terms of follow-up time (61 vs 63 months, P = 0.335). According to the Kaplan-Meier survival analysis, the 5-year BCR-free survival rate was statistically significantly lower in the upgraded group compared to the nonupgraded group (100.0% vs 96.7%, P = 0.047, Figure 1a).

DISCUSSION
Multiple studies have addressed the frequent clinical observation that prostate biopsy GS and RP GS will be discordant [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] in 12%-92% of cases. The published explanations could include repeat review of specimens [17][18][19]21,22,24,[26][27][28] by dedicated genitourinary pathologist, 13,16,22,24 or the major revision of the Gleason grading system at the International Society of Urological Pathology (ISUP) consensus conference in 2005. 8 Our study suggests that, beyond interpretation issues, the acquisition of the rest of the gland provides such a different sample size than biopsy that the high prevalence of mixed Gleason 3 and 4 pattern disease results in a regression to the mean GS7, even when biopsies indicate the more extreme GS 6 or GS 8. Our data suggest a difference between low-volume GS 6 and high-volume GS 6; although of interest, the high correlation of high-volume GS 6 to upgrading did not result in a large difference in recurrence rate.
At the other extreme, nonupgraded GS 6 did not recur, in keeping with the modern concept of pathologic GS 6 not demonstrating the definition of a malignancy. Moving forward, our study explores two follow-up areas on the impact of GS changes: (1) would they change clinical management and (2) would they change biochemical recurrence rates? Clinicians may recommend additional testing -with added expense -to refine clinical decision-making. In some cases, the biopsy GS may be accepted at face value for clinical decision-making. While MRI and targeted biopsy may be an improved method to obtain the correct pathologic GS, 29-31 our study can provide some useful preliminary information and patient selection guidance.
At the low end of the scale, GS (3+3) is often selected for AS, although a surprising number of our patients who opted for surgery were upgraded to GS (3+4) or higher (70.9%) overall. This rate of upgrading has been described before 27 and, in our case, includes a cohort of biopsy GS 6 cases selecting surgery where 48.9% were PRIAS candidates. Truong et al. 23 evaluated all the AS protocols including PRIAS criteria and reported an upgrade rate of 30.9% (P < 0.0001) in patients eligible for PRIAS criteria. Fortunately, the majority of these upgrades were only to GS (3+4) (90.9%) with only 3.4% BCR. We would hypothesize, therefore, that, although giving the pathologist "the rest of the gland" is highly correlated with finding Gleason pattern 4 somewhere, the biology of the disease in the intermediate-term follow-up (5 years) is almost benign. In pure GS 6 confirmed at surgery, BCR was not observed.
Nevertheless, our statistical modeling shows various predictors for upgraded Gleason score at RP: higher age, clinical stage, PSAD, and   presence of HGPIN and/or ASAP. In Table 4, we illustrate the spectrum of GS 6 biopsies and how number of cores+ and length of tumor foci can correlate with a >90% chance of upgrading. The ideal patient for lowest risk of upgrading would be age under 60 years, 1 core with <2 mm, PSA <4.3 ng ml -1 , PSAD <0.13 ng ml -1 , cT1c, and Hispanic. On the other hand, a very young patient with multiple risk factors for upgrading might be counseled as a GS (3+4). Then, the patient and clinician can focus upon whether or not that is enough information to make a decision versus add MRI and/or genomic testing to break the tie between surveillance and intervention.
These are "treated" statistics, and if the decision is for surveillance, then GS 7 still has to be discussed in terms of its success rates in the long term. Dall'Era and Klotz 35 have shown that some intermediate-risk patients are at higher risk of metastases on surveillance, and the ProTect trial 36 also showed differences in metastases compared to treated cohorts. Perhaps, the recently published PRECISION 30 trial will lead to greater numbers of MRI before primary biopsy such that more patients are allocated to the correct GS at first biopsy. Indeed, the study by Radtke et al. 31 showed >90% accuracy in identifying index lesions. Therefore, in the circumstance of available highly expert MRI image acquisition, interpretation, and fusion (possibly cognitive) biopsy techniques, the final grade issues should shift in a favorable direction: (1) MRfusion biopsied patients with GS 7 will more likely be identified that way at biopsy and (2) MR-fusion biopsied patients with GS 6 should have lower risk of upgrading.
On the high end of the scale, most guidelines suggest that high-risk PCa consider active intervention as well as clinical trials. High-risk patients choosing radiation would have different androgen deprivation therapy (ADT) recommendations compared to intermediate-risk patients -24 months versus 6 months. [37][38][39] It certainly makes sense that biopsy pattern 5 will likely correlate with RP pattern 5 -usually a final score of 4+5 or 5+4. However, with biopsy GS (4+4), all you need is additional areas of pattern 3 in the predominant foci to downgrade it to 4+3 or 3+4. In addition, biopsy GS (4+4) patients may have that finding in isolation, or with other positive cores showing lower grade. We considered both possibilities, and the overall downgrading rate was 50.5% with multiple prognostic factors shown in Table 6 and 7. Moussa et al. 12 and Epstein et al. 26 also reported a similar rate of downgrade from GS 8 as 50.0% and 51.3%, respectively. Moussa et al. 12 evaluated the downgrade factors generally    for all GS and found a significant relation with higher prostate volume, more obtained biopsy cores, and low maximum percentage cancer in any core. Epstein et al. 26 detected lower PSA level and lower maximum percentage of cancer per core as significant predictors for downgrade for any biopsy GS. Although having a single core of GS (4+4) was prognostic for downgrading, none of our features held up in multivariate analysis -perhaps sample size limiting.
Five-year BCR shown in Figure 1b was improved by 20.3% in the downgraded group. These might be more subtle aspects of clinical utility, as patients seem to merit treatment either way, but perhaps useful statistics for further study and refinement for defining more truly high-risk patients for clinical trials and/or radiation candidates for reduced ADT exposure. On the other hand, it is a reasonable argument that the 28.9% 5-year BCR of downgraded high-risk cases merits consideration for combination therapy and/or trials. Our study is limited by being retrospective, single institution/tertiary referral location, and specific to the biases of patients selecting RP (i.e., age, comorbidity, etc.). Our follow-up metrics are limited to BCR given the more recent era of study. BCR may be associated with metastatic progression and further survival endpoints, but with heterogeneous timing and significance -these would be areas for future study.

CONCLUSION
In counseling men with clinically localized prostate cancer, the odds of GS change should be presented, and certain men with high volume GS 6 or low volume GS 8 managed as if they are GS 7.