Heterogeneity of contemporary grade group 4 prostate cancer in radical prostatectomy specimens.

PURPOSE: The aim was to evaluate the prognostic role of sub-categories of ISUP 4 prostate cancer (PCa) on final pathology, and assess the tumor architecture prognostic role for predicting biochemical recurrence (BCR) after radical prostatectomy. METHODS: From a prospectively-maintained database, we included 370 individuals with ISUP 4 on final pathology. The main outcomes were to evaluate the relationship between different ISUP patterns within the group 4 with pathological and oncological outcomes. Binary logistic regression and Kaplan-Meier estimator were used to evaluate the role of the different categories (3 + 5, 4 + 4, 5 + 3) and tumor architecture (intraductal and/or cribriform) on pathological and oncological outcomes. RESULTS: Among the 370 individuals with ISUP considered for the study, 9, 85 and 6% had grade 3 + 5, 4 + 4 and 5 + 3 PCa, respectively. Overall, 74% had extracapsular extension, while lymph node invasion (LNI) was documented in 9%. A total of 144 patients experienced BCR during follow-up. After adjusting for PSA, pT, grade group, LNI and positive surgical margins (PSM), grade 3 + 5 was a protective factor (HR: 0.30, 95% CI: 0.13,0.68, p = 0.004) in predicting BCR relative to grade 4 + 4. Intraductal or cribriform architecture was correlated with BCR (HR: 5.99, 95% CI: 2.68, 13.4, p < 0.001) after adjusting for PSA, pT, grade group, LNI and PSM. CONCLUSIONS: Patients with tumor grade 3 + 5 had better pathological and prognostic outcomes compared to 4 + 4 or 5 + 3. When accounting for tumor architecture, the sub-stratification into subgroups lost its prognostic role and tumor architecture was the sole predictor of poorer prognosis in terms of biochemical recurrence.

Presence of biopsy Gleason pattern 5 + 3 is associated with higher mortality after radical prostatectomy but not after external beam radiotherapy compared to other Gleason Grade Group IV patterns.

BACKGROUND: We hypothesized that Gleason Grade Group (GGG) IV patients treated with radical prostatectomy (RP) or external beam radiotherapy (EBRT) exhibit different cancer-specific mortality (CSM) rates according to underlying Gleason patterns (GP): 4 + 4 versus 3 + 5 versus 5 + 3. MATERIALS AND METHODS: We identified all GGG IV patients treated with either RP or EBRT within the Surveillance, Epidemiology, and End Results 2004-2016 database. The effect of biopsy GP on CSM (3 + 5 vs. 4 + 4 vs. 5 + 3) was tested in Kaplan-Meier and multivariable competing risks regression models (adjusted for PSA, age at diagnosis, cT-, and cN-stage). RESULTS: Of 26,458 GGG IV patients, 14,203 (53.7%) were treated with EBRT and 12,255 (46.3%) with RP. Of RP patients, 15.3 versus 81.2 versus 3.4% exhibited biopsy GP 3 + 5 versus 4 + 4 versus 5 + 3 and respective 10-year CSM rates were 6.5 versus 6.2 versus 12.6% (p < .001). In multivariable analyses addressing RP patients, GP 5 + 3 was associated with two-fold higher CSM rate than GP 4 + 4 (p < .001), but not GP 3 + 5 (p = .1). Of EBRT patients, 7.6 versus 89.8 versus 2.6% exhibited biopsy GP 3 + 5 versus 4 + 4 versus 5 + 3 and respective 10-year CSM rates were 12.2 versus 13.8 versus 17.8% (p < .001). In multivariable analyses addressing EBRT patients, no CSM differences according to GP were observed (all p ≥ .4). CONCLUSION: In GGG IV RP candidates, the presence of biopsy GP 5 + 3 purports a significantly higher CSM than in GP 4 + 4 or 3 + 5. In GGG IV EBRT candidates, no significant CSM differences according to GP were recorded.

Grade group 4 prostate cancer without intraductal carcinoma on biopsy is more likely to be downgraded on prostatectomy than with intraductal carcinoma.

In this study, we investigated the association between intraductal carcinoma of the prostate (IDCP) along with several histopathological features on prostate biopsy and downgrading of grade group 4 (GG4) prostate cancer (PCa) in patients with the highest grade tumor of GG4 PCa in at least one core. A total of 29 cases had the highest grade tumor of GG4 PCa and radical prostatectomy performed between 2016 and 2021. IDCP was detected in 11 out of 29 cases on biopsy. The cases without IDCP were more likely to be downgraded on prostatectomy than with IDCP, with statistical significance (88.9% vs 36.4%, p = 0.003). The proportions of the highest-grade tumors by length and cores involved, average numbers of PCa-positive cores, and mean patient's age did not differ between cases that were downgraded and not downgraded at prostatectomy. Our results suggest that the absence of IDCP on biopsy could be a predictor of downgrading at prostatectomy for patients with the highest grade tumor of GG4 PCa.

Novel Transcriptomic Interactions Between Immune Content and Genomic Classifier Predict Lethal Outcomes in High-grade Prostate Cancer.

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naïve biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype-ICSHigh/DecipherHigh. Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICSHigh/DecipherHigh subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICSHigh/DecipherHigh subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76-10.6; p ≤ 0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18-26.94; p ≤ 0.0001) as compared with ICSLow/DecipherLow. The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. PATIENT SUMMARY: In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities.

Prognostic Differences in ISUP Grade Group 4: a Systematic Review and Meta-Analysis.

The ISUP (Internal Society of Urologic Pathology) recently adopted a five-tiered prognostication system. There is evidence to suggest that the ISUP grade group 4 is a heterogeneous entity regarding prognosis. Our aim was to systematically examine the existing evidence to determine if outcome differences exist within the ISUP grade group 4. A systematic search of the literature for all studies examining the heterogeneity of the ISUP grade group 4 was conducted. Available studies were combined with meta-analysis to evaluate prognostic differences within the ISUP grade group 4 measured by all-cause mortality (ACM) and the prostate cancer-specific mortality (PCSM). Eight studies were identified and utilised a variety of outcome measures to answer the question of heterogeneity within the ISUP grade group 4. Four of these studies examined prognosis using both ACM and PCSM. These were combined into a meta-analysis. The combined group of 5 + 3/3 + 5 had statistically significant higher ACM (hazard ratio [HR] 1.23, 95% confidence internal [Cl] 1.08-1.41) when compared to the 4 + 4 group. There was no difference in the PCSM between the two groups (HR 1.34, 95% CI 0.89-2.01). However, heterogeneity was high for this analysis secondary to a range of methodological differences. Our meta-analysis showed that Gleason grade 3 + 5/5 + 3 had higher ACM than Gleason grade group 4 + 4. Measures of PCSM were statistically insignificant, although heterogeneity was high. Evidence suggests that heterogeneity is likely, although inconclusive. Further studies with consistent methodologies are required to answer this question.

Gleason score 5 + 3 = 8 (grade group 4) prostate cancer-a rare occurrence with contemporary grading.

Grade Group (GG) 4 prostate cancer includes Gleason scores (GS) 3 + 5 = 8, 4 + 4 = 8, and 5 + 3 = 8. Some studies without pathology re-review of historical cohorts proposed that the presence of pattern 5 worsens prognosis compared to GS 4 + 4 = 8 cancer. We assessed how often historically graded GS 5 + 3 = 8 cancers retain this grade with contemporary grading recommendations. Sixteen prostate biopsies and 24 radical prostatectomies (RP) reported from 2005 to 2019 as GS 5 + 3 = 8 were re-reviewed and graded according to contemporary recommendations. In discrepant cases, an attempt was made to explain the different grading. One (6%) biopsy and 3 (12%) RPs remained GS 5 + 3 = 8 (GG4) after re-review. Two (12%) biopsies remained GG4 but were re-graded as GS 3 + 5 = 8 and 1 (4%) RP was reclassified as GS 4 + 4 = 8 (GG4). Eight (50%) biopsies and 15 (64%) RPs were upgraded to Gleason scores 9-10 (GG5). Five (32%) biopsies and 1 (4%) RPs were downgraded to Gleason score 7 (GG2 and 3). One (4%) RP showed GS 3 + 3 = 6 (GG1) cancer. Data from 2013-current from the 3 institutions were available to assess the incidence of GS 5 + 3 = 8 following re-review of the cases. Out of 14 359 biopsies with cancer and 6727 radical prostatectomy specimens, only 1 case (0.007%) and no cases (0%) were graded as GS 5 + 3 = 8, respectively. Reasons for grading discrepancies included: 1) assigning an overall common grade to separate needle cores or tumor nodules; 2) inclusion of <5% lower grade pattern into grading; and 3) misinterpretation of variant histology and patterns. Challenging patterns were poorly-formed glands, signet ring cell-like features, atrophic carcinoma, ductal carcinoma, and mucinous fibroplasia. GS 5 + 3 = 8 (GG4) cancer is very rare with contemporary grading. The reliability of conclusions from retrospective databases regarding the clinical significance of this grade combination without slide re-review is questionable.

ISUP Group 4 - a Homogenous Group of Prostate Cancers?

The International Society of Urological Pathology (ISUP) and the World Health Organisation have adopted a five-tiered prognostic grade group for prostate cancer in 2014. Grade group 4 is comprised of Gleason patterns 4 + 4, 3 + 5 and 5 + 3. Recent articles have suggested heterogeneity in their prognostic outcomes. We aimed to determine whether there was a difference in mortality outcomes within the ISUP 4 grouping, as identified on needle biopsy. A total of 4080 men who were diagnosed with non-metastatic (N0 M0) prostate cancer on biopsy with Gleason scores of 7, 8 and 9 were included. Multi-variable Cox Regression and Fine and Grey competing risk analysis were used to determine the All-Cause Mortality (ACM) and the Prostate Cancer Specific Mortality (PCSM) as a function of Gleason Scores (Gleason 3 + 4, 4 + 3, 4 + 4, 3 + 5/5 + 3, 9). Gleason score 4 + 4 was utilized as the referent. The 60 months' prostate cancer specific mortality with Gleason patterns 4 + 4 and 3 + 5/5 + 3 were 17% and 20% respectively (P < 0.01). Patients with 3 + 5/5 + 3 disease, had no statistically significant difference in the ACM (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [Cl] 0.68-1.4, p = 0.99) and PCSM risk (aHR 0.77, 95% Cl 0.47-1.2, p = 0.31) when compare with the referent group of patients. Patients with Gleason patterns 4 + 3 and 9 had statistically significant difference in their PCSM risk (aHR 0.70, 95% CI 0.54-0.91, P < 0.001 and aHR 1.5, 95% Cl 1.2-1.9, P < 0.001) when compared to the referent group. Our analysis suggest that ISUP group 4 is homogenous in terms of the all-cause mortality and the prostate cancer specific morality risk as differentiated by the presence of Gleason 5 score.