Impact of Gleason pattern 5 on prognosis for newly diagnosed metastatic hormone-sensitive prostate cancer with Gleason score ≥8.

OBJECTIVE: We evaluated the impact of Gleason pattern 5 presence on prognosis among de novo metastatic hormone-sensitive prostate cancer patients with a Gleason score ≥8. METHODS: The data of 559 patients diagnosed as metastatic hormone-sensitive prostate cancer with a Gleason score ≥8, who were initially treated with androgen deprivation therapy from 2008 to 2016, were retrospectively collected. Patients were divided into two groups as high and low volume based on the CHAARTED trial criteria. RESULTS: The median overall survival of the 559 metastatic hormone-sensitive prostate cancer patients with Gleason score ≥8 was 70 months, with a median follow-up period of 36 months. Gleason pattern 5 was confirmed in 341 patients (61.0%), in which primary Gleason pattern 5 was confirmed in 164 patients (29.3%). The number of patients with high metastatic volume group was 363 (64.9%). In total and high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival, but both Gleason pattern 5 and primary Gleason pattern 5 did not show a statistically significant difference. In the low-volume metastatic group, the median overall survival in patients with or without primary Gleason pattern 5 was 40 and 78 months, respectively. In multivariate analysis, only primary Gleason pattern 5 was an independent predictive factor for overall survival in the low-volume metastatic group (hazard ratio 2.76, 95% confidence interval 1.88-8.67; P = 0.0026). CONCLUSION: The presence of Gleason pattern 5 was not associated with overall survival in metastatic hormone-sensitive prostate cancer with a Gleason score ≥8. In low-metastatic volume metastatic hormone-sensitive prostate cancer, primary Gleason pattern 5 was a poor prognostic factor, which might show a separate treatment option for this group.

[Existence of pattern 5 on radical prostatectomy: poor prognostic factor associated with a lower biochemical recurrence-free survival]. / Existence de grade 5 sur pièce de prostatectomie totale: facteur de mauvais pronostic associé à une moindre survie sans récidive biologique.

OBJECTIVES: To analyze the impact of the existence of Gleason grade 5 on the adverse pathology and biochemical recurrence-free survival of patients. PATIENTS: Three hundred and seventy-two prostatectomies were performed between 1999 and 2011 in our institution for localised prostate adenocarcinoma. We examined the existence of grade 5 of the specimen to determine the reliability of prostate biopsies in the diagnosis of grade 5 and the association of grade 5 with other histoprognostic factors. Biochemical recurrence-free survival was analyzed according to the presence of grade 5 in the final specimen. RESULTS: In total, all histological data and biochemical recurrence-free survival were available for 321 patients who were included in the study. Sixty-eight had Gleason grade 5 (majority or third minority pattern) on the specimen while 253 had not. Grade 5, rarely diagnosed on biopsy (sensitivity=26.47 %) was correlated independently with the extracapsular extension (OR=2.1; CI 95 [1.1-3.9]), the seminal vesicle invasion (OR=3.8; CI 95 [1.7-8.7]) and positive surgical margins (OR=2.0; CI 95 [1.1-3.6]). Overall survival was similar in both groups but the biochemical recurrence-free survival was statistically lower in the presence of grade 5 (HR=3.7; CI 95 [1.8-7.6]). Biochemical recurrence-free survival was not different than grade 5 is predominant or third minority pattern (HR=1.01; CI 95 [0.3-2.8]). On multivariate analysis, grade 5 was an independent risk factor for biochemical recurrence (P=0.005) as well as seminal vesicle invasion (P=0.047). CONCLUSION: The existence of grade 5 in the surgical specimen whatever the percentage was a poor prognostic factor associated with increased tumor aggressiveness and reduced biochemical recurrence-free survival. LEVEL OF EVIDENCE: 5.

Comedonecrosis within conventional prostatic adenocarcinoma vs. intraductal carcinoma of the prostate: their clinical significance is not comparable.

It remains controversial if Gleason grade should be assigned to intraductal carcinoma of the prostate (IDC-P) and if the prognostic value of comedonecrosis associated with IDC-P is equivalent to that in conventional/invasive prostatic adenocarcinoma (CPA) as a Gleason grade 5 pattern. We herein assessed radical prostatectomy findings and postoperative outcomes in 287 patients with CPA exhibiting any Gleason pattern 5. Our cases were divided into 4 cohorts according to the absence or presence of necrosis within CPA and/or IDC-P: Cohort-1) no necrosis in CPA/IDC-P (n = 179; 62.4%); Cohort-2) necrosis only in CPA (n = 25; 8.7%); Cohort-3) necrosis only in IDC-P (n = 62; 21.6%); and Cohort-4) necrosis in both CPA and IDC-P (n = 21; 7.3%). Univariate analysis revealed patients with necrosis only in IDC-P (P < .001) or both CPA and IDC-P (P = .001) had a higher risk of progression than those with necrosis only in CPA, while the prognosis was comparable between the no necrosis group vs. the CPA only necrosis group (P = .680) or the IDC-P only necrosis group vs. the CPA/IDC-P necrosis group (P = .715). In a subgroup of patients exhibiting IDC-P (n = 198), the presence of IDC-P necrosis was still associated with a significantly higher progression risk, compared with CPA necrosis only. In multivariable analysis, necrosis only in IDC-P (vs. necrosis only in CPA) showed significantly worse progression-free survival (HR = 3.193, P = .003). IDC-P necrosis, as an independent predictor, was thus found to be associated with significantly worse oncologic outcomes, compared with necrosis only in CPA, and might therefore be better not to be simply considered as a grade 5 pattern.

Clonal relationships of adjacent Gleason pattern 3 and Gleason pattern 5 lesions in Gleason Scores 3+5=8 and 5+3=8.

Genomic studies have demonstrated a high level of intra-tumoral heterogeneity in prostate cancer. There is strong evidence suggesting that individual tumor foci can arise as genetically distinct, clonally independent lesions. However, recent studies have also demonstrated that adjacent Gleason pattern (GP) 3 and GP4 lesions can originate from the same clone but follow divergent genetic and morphologic evolution. The clonal relationship of adjacent GP3 and GP5 lesions has thus far not been investigated. Here we analyzed a cohort of 14 cases-11 biopsy and 3 radical prostatectomy specimens-with a Gleason score of 3 + 5 = 8 or 5 + 3 = 8 present in the same biopsy or in a single dominant tumor nodule at radical prostatectomy. Clonal and subclonal relationships between GP3 and GP5 lesions were assessed using genetically validated immunohistochemical assays for ERG, PTEN, and P53. 9/14 (64%) cases showed ERG reactivity in both GP3 and GP5 lesions. Only 1/14 (7%) cases showed a discordant pattern with ERG staining present only in GP3. PTEN expression was lost in 2/14 (14%) cases with perfect concordance between GP5 and GP3. P53 nuclear reactivity was present in 1/14 (7%) case in both GP5 and GP3. This study provides first evidence that the majority of adjacent GP3 and GP5 lesions share driver alterations and are clonally related. In addition, we observed a lower-than-expected rate of PTEN loss in GP5 in the context of Gleason score 3 + 5 = 8 or 5 + 3 = 8 tumors.

Pattern of Biopsy Gleason Grade Group 5 (4 + 5 vs 5 + 4 vs 5 + 5) Predicts Survival After Radical Prostatectomy or External Beam Radiation Therapy.

BACKGROUND: Previous cancer-specific mortality (CSM) analyses for different Gleason patterns in Gleason grade group (GGG) 5 cancer were limited by sample size. OBJECTIVE: To test for differences in CSM according to biopsy GG 5 patterns (4 + 5 vs 5 + 4 vs 5 + 5) among patients undergoing radical prostatectomy (RP) or external beam radiation therapy (EBRT). DESIGN, SETTING, AND PARTICIPANTS: Patients in the Surveillance, Epidemiology and End Results database treated with RP and EBRT (2004-2016) were identified and stratified according to Gleason 4 + 5 versus 5 + 4 versus 5 + 5. INTERVENTION: RP or EBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Kaplan-Meier and multivariable Cox regression models predicting CSM were constructed. RESULTS AND LIMITATIONS: Of 17 263 eligible patients with GG 5 cancer at biopsy (RP: n = 7208; EBRT: n = 10 055), 12 705 had Gleason 4 + 5, 3302 had Gleason 5 + 4, and 1256 had Gleason 5 + 5 disease. Median age, prostate-specific antigen (PSA) at diagnosis, and advanced cT and cN stages significantly differed by Gleason pattern (Gleason 4 + 5 vs 5 + 4 vs 5 + 5; all p < 0.001). The 10-yr CSM rate was 18.2% for Gleason 4 + 5, 28.0% for Gleason 5 + 4, and 39.1% for Gleason 5 + 5 (p < 0.001). In multivariable analyses for the entire cohort adjusted for PSA, age at diagnosis, and cT and cN stage, Gleason 5 + 4 and Gleason 5 + 5 were associated with 1.6- and 2.2-fold higher CSM, respectively, relative to Gleason 4 + 5. In addition, Gleason 5 + 4 and Gleason 5 + 5 were associated with 1.6- and 2.5-fold, and 1.5- and 2.1-fold higher CSM rates in the RP and EBRT subgroups, respectively, relative to Gleason 4 + 5 (all p < 0.001). CONCLUSIONS: For patients with biopsy GG 5 prostate cancer treated with RP or EBRT, there are important CSM differences by Gleason pattern (4 + 5 vs 5 + 4 vs 5 + 5). Ideally, the individual Gleason pattern should be considered in pretreatment risk stratification. PATIENT SUMMARY: For patients with grade 5 prostate cancer, we found differences in cancer-specific death rates according to the pattern of abnormal cells in the prostate, called the Gleason score. The highest death rate was found for a Gleason pattern score of 5 + 5, followed by Gleason 5 + 4 and then Gleason 4 + 5. These differences were observed for both patients who were treated with prostate removal and patients who underwent radiotherapy.

Gleason Pattern 5 is a Possible Pathologic Predictor for Biochemical Recurrence after Laparoscopic Radical Prostatectomy

Objective: Several prognostic factors for biochemical recurrence after radical prostatectomy have been reported, including initial prostate-specific antigen level, Gleason score, positive surgical margin, and seminal vesicle invasion. Here we investigate whether Gleason pattern 5 is a predictor for biochemical recurrence. Methods: This retrospective study included 168 patients who underwent laparoscopic radical prostatectomy from 2006 to 2015. The relationship between biochemical recurrence after laparoscopic radical prostatectomy and the presence of Gleason pattern 5, even as a tertiary pattern, was investigated. Biochemical recurrence was defined when the prostate-specific antigen level rose to >0.2 ng/ml after having decreased to <0.1 ng/ml following laparoscopic radical prostatectomy. Biochemical recurrence-free survival was estimated by the Kaplan-Meier method. Multivariate analysis was performed using a Cox proportional hazards regression model. Results: The median age was 66 years, median initial prostate-specific antigen level was 6.9 ng/ml, and median follow-up period was 47.3 months. Biochemical recurrence was recognized in 27 patients (16.1%) after laparoscopic radical prostatectomy, and 5-year biochemical recurrence-free survival was 78.6%. Gleason pattern 5 was noted in 5 patients as the primary pattern, in 10 as the secondary pattern, and in 5 as the tertiary pattern. According to multivariate analysis, presence of Gleason pattern 5 (HR = 4.75, p=0.001) and positive surgical margin (HR = 4.66, p=0.001) were independent predictive factors for biochemical recurrence-free survival. Conclusion: Gleason pattern 5 appears to be an important predictive factor for biochemical recurrence after laparoscopic radical prostatectomy.

Comparison of prostatic adenocarcinoma Gleason 5 and intraductal carcinoma of the prostate with tumor necrosis. A morphometric study.

Intraductal carcinoma of the prostate(IDCP) is defined as a solid or cribriform neoplastic growth confined to ducts and acini, with preservation of the basal cell layer. Since IDCP can often present tumor necrosis (TN), it should be distinguished from Gleason 5 (GP5) invasive adenocarcinoma for staging and clinical purposes. In the present study we reviewed 344 radical prostatectomies performed at our institution and selected all cases with either >5% GP5 or IDCP for assessment of TN on histology slides (n = 59). A total of 19 cases with TN were identified, and morphology, size, location, and histoarchitecture of the lesions with TN were recorded. Subsequently, the corresponding sections were stained with a basal cell immunomarker (P63), and lesions with TN were assigned to IDCP or invasive carcinoma GP5 for comparison. Our results show that a branched shape and size 501-1000 µm are more common in IDCP, while a size >1000 µm and location within 1 mm of the periprostatic soft tissue are significantly more prevalent in invasive adenocarcinoma GP5. These features, however, usually cannot be assessed in core biopsies. In this setting, the utilization of immunohistochemistry is warranted to differentiate IDCP and GP5 with necrosis.

Impact of Gleason Pattern 5 on outcomes of patients with prostate cancer and iodine-125 prostate brachytherapy.

BACKGROUND: The Gleason grading system is a powerful predictor of prostate cancer (PCa) prognosis. Gleason scores (GS) of 8-10 are considered as a single high-risk grade category, and Gleason Pattern 5 (GP5) predicts biochemical recurrence. We report the clinical outcomes of patients treated with 125I prostate brachytherapy for clinically localized PCa and prognosis in the presence or absence of GP5. METHODS: We enrolled 316 patients with T1c-T2N0M0 PCa and undergoing prostate brachytherapy treatment. All patients were followed up for ≥ 1 year. The primary endpoint was biochemical recurrence-free survival. Biochemical recurrence was defined by the Phoenix criteria. Survival curves were calculated by the Kaplan-Meier method, and the prognostic impact of biochemical recurrence was analyzed using a Cox proportional hazards model. RESULTS: The 5-year biochemical recurrence-free survival rate for all patients was 95.2%, and according to the D'Amico risk classification criteria, the rates were 98.7% for patients in low-risk, 96.9% in intermediate-risk, and 81.1% in high-risk groups (P < 0.0001). The 5-year biochemical recurrence-free survival rates for patients with GS8 or GS9-10 were 87.7% and 61.5%, respectively (P = 0.0057). Multivariate analysis found that GS and clinical T stage were independent predictors of biochemical recurrence. CONCLUSIONS: The presence of GP5 in GS9-10 prostate cancer has a worse prognosis than GS8 prostate cancer in the absence of GP5 for patients undergoing prostate brachytherapy.

Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5.

PURPOSE: To investigate the impact of Gleason pattern 5 (GP5) prostate cancer after either external beam radiotherapy (EBRT) or the combination of EBRT with low-dose rate brachytherapy boost (combo). METHODS AND MATERIALS: Between 1998 and 2008, 467 patients with National Comprehensive Cancer Network high-risk prostate cancer were treated with EBRT (n = 326) or combo (low-dose rate to 90-108 Gy using I-125 followed by EBRT) (n = 141). Freedom from biochemical failure, freedom from metastasis (FFM), cancer-specific survival (CSS), and overall survival were evaluated. RESULTS: Combo patients were younger (66 vs. 72 years, p < 0.001) and had fewer comorbidities (Charlson comorbidity index 3.7 vs. 4.4, p < 0.001). EBRT patients had higher tumor stages (T3-4: 30% vs. 21%, p = 0.03) and lower Gleason scores (8-10: 61% vs. 75%, p = 0.01). Androgen deprivation therapy use was similar between cohorts (85% vs. 87%, p = 0.5), but EBRT patients had longer androgen deprivation therapy use (median 14 vs. 12 months, p = 0.05). GP5 predicted worse FFM (p < 0.001, hazard ratio [HR] 3.3, 95% confidence interval [CI]1.8-6.2]) and CSS (p < 0.001, HR 5.9, 95% CI 2.7-12.9) for the EBRT group, but not for the combo group (p = 0.86, HR 0.48, 95% CI 0.1-2.4 for metastasis and p = 0.5, HR 1.6, 95% CI 0.33-8.0 for CSS). In those with GP5 (n = 143), combo was associated with improved outcomes in all endpoints. On univariate analysis, 5-year outcomes for combo vs. EBRT were as follows: freedom from biochemical failure 89% vs. 65%, FFM 89% vs. 67%, CSS 93% vs. 78%, and overall survival 88% vs. 67% (p < 0.05 for all). CONCLUSION: Combo was associated with improved outcomes for men with GP5 prostate cancer. This highlights the importance of local therapy, especially in patients with the highest pathologic grade disease.

Validation of tertiary Gleason pattern 5 in Gleason score 7 prostate cancer as an independent predictor of biochemical recurrence and development of a prognostic model.

OBJECTIVE: To validate the biological and prognostic value of tertiary Gleason pattern 5 (TGP5) in patients with Gleason score 7 (GS 7) prostate cancer (PCa) and to develop a prognostic model to identify the high-risk group of patients with TGP5. MATERIAL AND METHODS: We retrospectively reviewed the data from 4,146 patients with localized (pT2-3 N0 M0) GS 7 PCa treated by radical prostatectomy (RP) without adjuvant therapy. The primary end point was biochemical recurrence (BCR), and the secondary one was to build a bootstrap-corrected multivariable Cox model. RESULTS: Of the 4,146 patients, 416 (10%) had a TPG5 in the RP specimen. TGP5 was associated with BCR in both univariable and multivariable analyses that adjusted for the effects of standard pathological features (P<0.001). A prognostic model based on preoperative prostate-specific antigen levels (<10 vs.≥10ng/ml), primary and secondary Gleason pattern (3+4 vs. 4+3), pathological tumor category (pT2/pT3a vs. pT3b), and surgical margin status (R0 vs. R+) stratified patients with a discrimination of 72.2%. Patients in the low-risk group had a 5-year BCR-free survival rate of 76.3% compared with only 18.5% for those in the high-risk group (P<0.001). CONCLUSIONS: Knowledge of TGP5 improves our prognostication of patients with GS 7 PCa treated with RP. We developed a statistical tool to help identify the patients with TGP5 who are at the highest risk of BCR after RP, thereby helping with the clinical decision making regarding adjuvant trials and follow-up scheduling.

Adenocarcinoma of the prostate with Gleason pattern 5 on core biopsy: frequency of diagnosis, morphologic subpatterns, and relation to pattern distribution based on the modified Gleason grading system.

Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma (PCa) on core biopsy (NBX) is critical because it is associated with disease progression and the worst clinical outcome. We evaluated 1557 consecutive and prospectively collected NBXs to determine the frequency of diagnosis, morphologic subpatterns, and their relation to the amount and pattern distribution of GP5 PCa based on the 2005 modified Gleason grading system. Tertiary GP5 was upgraded to a secondary pattern to derive the final Gleason score. GP5 accounted for 6% of all NBXs and 14% of PCa cases. GP5 PCas were associated with high-risk preoperative clinical and biopsy characteristics, regardless of the amount of GP5. Most patients (85%) with % GP5 greater than 5% of PCa had the final Gleason score of 9 to 10, compared with % GP5 of 5% or less of PCa (P < .0001). The morphologic subpatterns of GP5 PCas were as follows: infiltrating cords (96%), single cells (76%), solid sheets (29%), and comedocarcinoma (2%). Infiltrating cords and single-cell patterns frequently coexisted (76%). The GP5 was distributed in a tertiary (66%), followed by secondary (32%) and primary (2%) components of PCa. Infiltrating cords and single cells were the 2 most frequently encountered patterns, specifically when GP5 involved 5% or less of PCa and represented secondary or tertiary component of PCa. GP5 PCa is a relatively frequent presentation in the contemporary NBX practice. Because of its important prognostic and therapeutic implications, pathologists must be aware of its varied morphologic presentations and to the fact that most cases with GP5 represent a tertiary component of PCa.

Long-term outcomes of prostate cancer patients with Gleason pattern 5 treated with combined brachytherapy and external beam radiotherapy.

PURPOSE: Recent reports have suggested relatively poor prognosis for prostate cancer patients with Gleason pattern 5 treated with dose-escalated external beam radiotherapy (XRT) and androgen deprivation therapy (ADT). We present the largest series of men with high-risk, Gleason pattern 5 prostate cancer treated with permanent interstitial brachytherapy and XRT. METHODS AND MATERIALS: Between April 1995 and December 2008, 329 consecutive patients with National Comprehensive Cancer Network high-risk disease were treated with permanent interstitial brachytherapy. Most received XRT and ADT. Median followup was 7.2 years. The cause of death was determined for each deceased patient. Multiple clinical, treatment, and dosimetric parameters were evaluated for impact on the evaluated survival parameters. RESULTS: At 10 years, biochemical progression-free survival, cause-specific survival (CSS), and overall survival for the group of high-risk patients as a whole was 91.1%, 95.5%, and 72.5%, respectively. There was no difference in biochemical progression-free survival between men with and without Gleason pattern 5 (89.7% vs. 91.8%; p=0.56). However, men with Gleason pattern 5 had lower prostate cancer CSS (90.3% vs. 98.1%; p=0.011). There was no difference in overall survival comparing men with and without Gleason pattern 5 disease (67.7% vs. 75.4%; p=0.14). CONCLUSIONS: Men with high-risk, Gleason pattern 5 histology treated with brachytherapy and XRT have excellent long-term outcomes, which compare favorably to dose-escalated XRT/ADT series without brachytherapy. Nonetheless, Gleason pattern 5 results in lower CSS than high-risk disease without Gleason pattern 5.