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1.  Prognostic Gleason grade grouping: data based on the modified Gleason scoring system 
BJU international  2013;111(5):753-760.
Objective
• To investigate pathological and short-term outcomes since the most recent Gleason system modifications by the International Society of Urological Pathology (ISUP) in an attempt to divide the current Gleason grading system into prognostically accurate Gleason grade groups.
Patients and Methods
• We queried the Johns Hopkins Radical Prostatectomy Database (1982–2011), approved by the institutional review board, for men undergoing radical prostatectomy (RP) without a tertiary pattern since 2004 and identified 7869 men.
• Multivariable models were created using preoperative and postoperative variables; prognostic grade group (Gleason grade ≤6; 3 + 4; 4 + 3; 8; 9–10) was among the strongest predictors of biochemical recurrence-free (BFS) survival.
Results
• Significant differences were noted among the Gleason grade groups at biopsy; differences were noted in the race, PSA level, clinical stage, number of positive cores at biopsy and the maximum percentage of positive cores among the Gleason grade groups at RP.
• With a median (range) follow-up of 2 (1–7) years, 5-year BFS rates for men with Gleason grade ≤6, 3 + 4, 4 + 3, 8 and 9–10 tumours at biopsy were 94.6, 82.7, 65.1, 63.1 and 34.5%, respectively (P < 0.001 for trend); and 96.6, 88.1, 69.7, 63.7 and 34.5%, respectively (P < 0.001), based on RP pathology.
Conclusions
• The 2005 ISUP modifications to the Gleason grading system for prostate carcinoma accurately categorize patients by pathological findings and short-term biochemical outcomes but, while retaining the essence of the Gleason system, there is a need for a change in its reporting to more closely reflect tumour behaviour.
• We propose reporting Gleason grades, including prognostic grade groups which accurately reflect prognosis as follows: Gleason score ≤6 (prognostic grade group I); Gleason score 3+4=7 (prognostic grade group II); Gleason score 4+3=7 (prognostic grade group III); Gleason score 4+4=8 (prognostic grade group (IV); and Gleason score 9–10 (prognostic grade group (V).
doi:10.1111/j.1464-410X.2012.11611.x
PMCID: PMC3978145  PMID: 23464824
Gleason grade; prostate carcinoma; radical prostatectomy
2.  Gleason grade remains an important prognostic predictor in men diagnosed with prostate cancer while on finasteride therapy 
BJU international  2005;95(4):509-512.
OBJECTIVE
To evaluate men treated with finasteride for lower urinary tract symptoms, who subsequently were diagnosed with prostate cancer and had a radical prostatectomy (RP) at our institution, to determine if finasteride therapy prevented accurate Gleason grade assignment and prediction of biochemical recurrence.
PATIENTS AND METHODS
Between May 1996 and July 2003, 45 men were identified who had RP and had previously been treated with finasteride for ≥6 months before the diagnosis of prostate cancer. Clinical and pathological information was gathered from a RP database. Serum prostate-specific antigen (PSA) level, duration of finasteride therapy, biopsy Gleason grade, clinical stage, RP Gleason grade and pathological stage were reviewed. Freedom from recurrence was predicted using validated nomograms before and after RP, and compared against actuarial 5-year freedom from recurrence using the Kaplan-Meier method.
RESULTS
The mean duration of finasteride therapy before diagnosis was 23.6 months, the mean serum PSA (doubled to account for finasteride use) 11.02 ng/mL and mean biopsy Gleason score 6. When comparing the biopsy and RP specimen Gleason score, it was downgraded by 1 point in six men, upgraded by 1 point in eight, and upgraded by 2 points in one. The Gleason score was constant in 30 patients. The nomograms predicted freedom from recurrence in 83% and 85%, respectively; the 5-year actuarial freedom from recurrence was 86%.
CONCLUSION
Finasteride does not appear to compromise the assignment of Gleason grade for use in prediction tools before or after RP in men undergoing prostate biopsy or RP. The actuarial 5-year freedom from recurrence was similar to that predicted by the validated nomograms. Gleason grade remains an important prognostic predictor in men treated with finasteride and undergoing RP for clinically localized prostate cancer.
doi:10.1111/j.1464-410X.2005.05375.x
PMCID: PMC1939940  PMID: 15705069
prostate cancer; finasteride; Gleason grade
3.  Tertiary Gleason Patterns and Biochemical Recurrence After Prostatectomy: Proposal for a Modified Gleason Scoring System 
The Journal of urology  2009;182(4):1364-1370.
Purpose
We investigated the relationship between the tertiary Gleason component in radical prostatectomy specimens and biochemical recurrence in what is to our knowledge the largest single institution cohort to date.
Materials and Methods
We evaluated data on 3,230 men who underwent radical prostatectomy at our institution from 2000 to 2005. Tertiary Gleason component was defined as Gleason grade pattern 4 or greater for Gleason score 6 and Gleason grade pattern 5 for Gleason score 7 or 8.
Results
Biochemical recurrence curves for cancer with tertiary Gleason component were intermediate between those of cancer without a tertiary Gleason component in the same Gleason score category and cancer in the next higher Gleason score category. The only exception was that Gleason score 4 + 3 = 7 with a tertiary Gleason component behaved like Gleason score 8. The tertiary Gleason component independently predicted recurrence when factoring in radical prostatectomy Gleason score, radical prostatectomy stage and prostate specific antigen (HR 1.45, p = 0.029). Furthermore, the magnitude of the tertiary Gleason component effect on recurrence did not differ by Gleason score category (p = 0.593).
Conclusions
Although the tertiary Gleason component is frequently included in pathology reports, it is routinely omitted in other situations, such as predictive nomograms, research studies and patient counseling. The current study adds to a growing body of evidence highlighting the importance of the tertiary Gleason component in radical prostatectomy specimens. Accordingly consideration should be given to a modified radical prostatectomy Gleason scoring system that incorporates tertiary Gleason component in intuitive fashion, including Gleason score 6, 6.5 (Gleason score 6 with tertiary Gleason component), 7 (Gleason score 3 + 4 = 7), 7.25 (Gleason score 3 + 4 = 7 with tertiary Gleason component), 7.5 (Gleason score 4 + 3), 8 (Gleason score 4 + 3 with tertiary Gleason component or Gleason score 8), 8.5 (Gleason score 8 with tertiary Gleason component), 9 (Gleason score 4 + 5 or 5 + 4) and 10.
doi:10.1016/j.juro.2009.06.048
PMCID: PMC4342045  PMID: 19683280
prostate; prostatic neoplasms; prostatectomy; surgical pathology; prognosis
4.  Factors predicting Gleason score 6 upgrading after radical prostatectomy 
Objectives
Prostate cancer Gleason score 6 is the most common score detected on prostatic biopsy. We analyzed the clinical parameters that predict the likelihood of Gleason score upgrading after radical prostatectomy.
Methods
The study population consisted of 241 patients who underwent radical retropubic prostatectomy between Feb 2002 and Dec 2007 for Gleason score 6 adenocarcinoma. The influence of preoperative parameters on the probability of a Gleason score upgrading after surgery was evaluated using multivariate logistic regression and ROC curves.
Results
Gleason score upgrade was found in 92 of 241 patients (38.2%). Multivariate logistic regression analysis showed that only percentage of cancer in dominant lobe and prostate weight were significant predictors for Gleason score upgrading (p = 0.043 and p = 0.006, respectively). ROC curves showed that prostate weight and PSA density were only two independent significant parameters for prediction of upgrade (AUC – 0.634, p <0.0001 and 0.604, p = 0.006, respectively). Gleason score upgrading was observed to be accompanied by significantly higher rates of extra prostatic extension (p <0.001) and seminal vesicle invasion (p = 0.002).
Conclusions
Almost forty percent of tumors graded Gleason 6 at biopsy are Gleason 7 at surgery. Upgraded tumors significantly associated with adverse pathological features. The probability of Gleason score upgrade can be predicted using prostate weight and PSA density as independent parameters.
doi:10.5173/ceju.2011.04.art3
PMCID: PMC3921736  PMID: 24578894
prostate cancer; Gleason score; biopsy; prostatectomy; upgrading
5.  Upgrading and Downgrading of Prostate Needle Biopsies: Risk Factors and Clinical Implications 
Urology  2007;69(3):495-499.
Background
The prostate biopsy Gleason grade frequently differs from the radical prostatectomy (RP) grade. Given the critical role needle biopsy plays in treatment decisions, we determined risk factors for upgrading and downgrading the prostate biopsy.
Methods
We determined the significant predictors of upgrading (higher RP grade than biopsy grade) and downgrading (lower RP grade than biopsy grade) among 1,113 men treated with RP between 1996 and 2005 within the SEARCH Database who underwent at least a sextant biopsy. Gleason sum was examined as a categorical variable of 2–6, 3+4, and ≥4+3.
Results
Overall, 299 men (27%) were upgraded, 123 (11%) were downgraded, and 691 (62%) had identical biopsy and pathological Gleason sum groups. Upgrading was associated with adverse pathology (p≤0.001) and risk of biochemical progression (p=0.001) while downgrading was associated more favorable pathology (p≤0.01) and a decreased risk of progression (p=0.04). On multivariable analysis, higher PSA (p<0.001), more biopsy cores with cancer (p=0.001), and obesity (p=0.003) were all significantly positively associated with upgrading while biopsy Gleason sum 3+4 (p=0.001) and obtaining ≥8 biopsy cores (p=0.01) were associated with less likelihood of upgrading.
Conclusions
Men who were upgraded were at greater risk of adverse pathology and biochemical progression. Men with “high-risk” cancer (higher PSA, more cores positive and obese) were more likely to be upgraded while obtaining more biopsy cores reduced the likelihood of upgrading.
doi:10.1016/j.urology.2006.10.036
PMCID: PMC3080253  PMID: 17382152
Prostate cancer; radical prostatectomy; Gleason; prostate biopsy; obesity
6.  Poorly Differentiated Prostate Cancer Treated With Radical Prostatectomy: Long-Term Outcome and Incidence of Pathological Downgrading 
The Journal of urology  2006;176(3):991-995.
Purpose:
Patients with high grade (Gleason score 8 to 10) prostate cancer on biopsy are at high risk for cancer recurrence after local treatment, such as radiation therapy and radical prostatectomy. We examined long-term outcomes in patients with high grade prostate cancer on biopsy who were treated with radical prostatectomy alone. We also investigated the impact on outcomes of changes in the radical prostatectomy Gleason score.
Materials and Methods:
Of 5,662 patients who underwent radical prostatectomy during 20 years 238 had a biopsy Gleason score of 8 to 10. We analyzed the rate of biochemical recurrence in this subgroup according to the Gleason grade of cancer in the radical prostatectomy specimen.
Results:
Ten-year biochemical recurrence-free probability in the cohort was 39%. However, 45% of patients (95% CI 38 to 51%) with Gleason score 8 to 10 cancer on biopsy had a Gleason score of 7 or less in the radical prostatectomy specimen. These patients had a 10-year biochemical recurrence-free probability of 56% compared to 27% in those with a final Gleason score that remained 8 to 10 (p = 0.0004). On multivariate analysis neither prostate specific antigen nor biopsy features, including total number of cores, number of cores with cancer and percent of cancer in the cores, was a significant predictor of downgrading. However, clinical stage and biopsy Gleason score were significant with 58% of cT1c and 51% of biopsy Gleason score 8 cancers downgraded. Almost 65% of cT1c Gleason score 8 cancers were downgraded compared to 11% of cT3 Gleason score 9 cancers.
Conclusions:
Patients diagnosed with poorly differentiated prostate cancer (Gleason score 8 to 10) on biopsy do not uniformly have a poor prognosis. Of the patients 39% remain free of cancer recurrence 10 years after radical prostatectomy. Of these cancers 45% have a lower Gleason score in the radical prostatectomy specimen and a correspondingly more favorable long-term outcome. Predictors of downgrading are lower clinical stage (cT1c) and Gleason score 8 in the biopsy specimen.
doi:10.1016/j.juro.2006.04.048
PMCID: PMC2239297  PMID: 16890678
prostate; prostatic neoplasms; prostatectomy; mortality; biopsy
7.  Progression and survival in prostatic adenocarcinoma: a comparison of clinical stage, Gleason grade, S-phase fraction and DNA ploidy. 
British Journal of Cancer  1994;70(2):309-314.
Clinical data were reviewed in 325 patients with prostatic adenocarcinoma followed up for a mean of 13 years. Paraffin-embedded tumour biopsy specimens from the primary tumours were available for flow cytometry (FCM) in 273 cases. Intra-tumour heterogeneity in DNA index (DI) was found in 4% of the tumours (54 cases were analysed). S-phase fraction (SPF) and DNA ploidy were significantly interrelated. Aneuploidy and high SPF were significantly related to both a high T category and high Gleason score. The progression in T1-2M0 tumours was related to Gleason score (P = 0.009), DNA ploidy (P = 0.006) and SPF (P = 0.007), while the Gleason score (P = 0.0013), DNA ploidy (P = 0.002) and SPF (P < 0.001) had prognostic value in univariate survival analysis. In the entire cohort, the T category (P < 0.001), M category (P < 0.001), Gleason score (P < 0.001), DNA ploidy (P < 0.001) and SPF (P < 0.001) were significant prognostic factors. In Cox's analysis, the M category (P < 0.001), Gleason score (P < 0.001), T category (P = 0.003), age (P = 0.001) and SPF (P = 0.087) were independently related to prognosis. In the T1-2M0 tumours, Gleason score (P < 0.001), T category (P = 0.022) and SPF (P = 0.058) were independent predictors. A novel classification system in which the DNA ploidy or SPF and the Gleason score were combined was found to be of significant prognostic value in all M0 tumours (P < 0.001). The results suggest that FCM can be used as an adjunct to conventional histological assessments for determination of the correct prognostic category in prostatic adenocarcinoma.
PMCID: PMC2033517  PMID: 8054280
8.  Can microfocal prostate cancer be regarded as low-risk prostate cancer? 
Prostate International  2013;1(4):158-162.
Purpose:
Prostate specific antigen (PSA) screening for prostate cancer has become widespread, the prostate biopsy technique has evolved, and the occurrence of low-risk prostate cancer has been increasing. Even low-risk patients may demonstrate disease upgrading or upstaging. We aimed to evaluate the clinical importance of a single microfocal prostate cancer at biopsy in patients subsequently treated with radical prostatectomy.
Methods:
A total of 337 cases of patients who underwent radical prostatectomy after prostate biopsies were retrospectively reviewed. Microfocal prostate cancer was defined as Gleason score 6 and a single positive core with ≤5% cancer involvement after the standard 12-core extended biopsy.
Results:
Of the 337 prostatectomy specimens, 22 (6.5%) were microfocal prostate cancer based on prostate biopsy. On final pathology, microfocal patients were found to have significant 45% Gleason score upgrading (P=0.02) and 27% positive surgical margins (P=0.04) despite low PSA, compared with the nonmicrofocal prostate cancer group. Gleason upgrading was significantly higher in the microfocal prostate cancer group (P=0.02), whereas Gleason downgrading was significantly higher in the nonmicrofocal prostate cancer group (P<0.01). Furthermore, biochemical recurrence rate was no different between microfocal and nonmicrofocal prostate cancer at mean 31 months (P=0.18). Overall, 13 of 22 cases (53.1%) in the microfocal prostate cancer group showed Gleason upgrading or stage upgrading.
Conclusions:
Based on higher rates of Gleason score upgrading or stage upgrading cases in microfocal prostate cancer group, compared with nonmicrofocal prostate cancer group, active surveillance should be cautiously applied to these patients.
doi:10.12954/PI.13028
PMCID: PMC3879053  PMID: 24392440
Prostate neoplasms; Biopsy; Low-risk prostate cancer; Prostatectomy
9.  Importance of prostate-specific antigen (PSA) as a predictive factor for concordance between the Gleason scores of prostate biopsies and RADICAL prostatectomy specimens 
Clinics  2013;68(6):820-824.
OBJECTIVE:
To evaluate the concordance between the Gleason scores of prostate biopsies and radical prostatectomy specimens, thereby highlighting the importance of the prostate-specific antigen (PSA) level as a predictive factor of concordance.
METHODS:
We retrospectively analyzed 253 radical prostatectomy cases performed between 2006 and 2011. The patients were divided into 4 groups for the data analysis and dichotomized according to the preoperative PSA, <10 ng/mL and ≥10 ng/mL. A p-score <0.05 was considered significant.
RESULTS:
The average patient age was 63.3±7.8 years. The median PSA level was 9.3±4.9 ng/mL. The overall concordance between the Gleason scores was 52%. Patients presented preoperative PSA levels <10 ng/mL in 153 of 235 cases (65%) and ≥10 ng/mL in 82 of 235 cases (35%). The Gleason scores were identical in 86 of 153 cases (56%) in the <10 ng/mL group and 36 of 82 (44%) cases in the ≥10 ng/mL group (p = 0.017). The biopsy underestimated the Gleason score in 45 (30%) patients in the <10 ng/mL group and 38 (46%) patients in the ≥10 ng/mL (p = 0.243). Specifically, the patients with Gleason 3 + 3 scores according to the biopsies demonstrated global concordance in 56 of 110 cases (51%). In this group, the patients with preoperative PSA levels <10 ng/dL had higher concordance than those with preoperative PSA levels ≥10 ng/dL (61% x 23%, p = 0.023), which resulted in 77% upgrading after surgery in those patients with PSA levels ≥10 ng/dl.
CONCLUSION:
The Gleason scores of needle prostate biopsies and those of the surgical specimens were concordant in approximately half of the global sample. The preoperative PSA level was a strong predictor of discrepancy and might improve the identification of those patients who tended to be upgraded after surgery, particularly in patients with Gleason scores of 3 + 3 in the prostate biopsy and preoperative PSA levels ≥10 ng/mL.
doi:10.6061/clinics/2013(06)16
PMCID: PMC3674287  PMID: 23778496
Gleason Score; Prostate-Specific Antigen (PSA); Prostate Biopsy; Radical Prostatectomy; Prostate Cancer
10.  Clinical and pathological variables that predict changes in tumour grade after radical prostatectomy in patients with prostate cancer 
Introduction:
Preoperative Gleason score is crucial, in combination with other preoperative parameters, in selecting the appropriate treatment for patients with clinically localized prostate cancer. The aim of the present study is to determine the clinical and pathological variables that can predict differences in Gleason score between biopsy and radical prostatectomy.
Methods:
We retrospectively analyzed the medical records of 302 patients who had a radical prostatectomy between January 2005 and September 2010. The association between grade changes and preoperative Gleason score, age, prostate volume, prostate-specific antigen (PSA), PSA density, number of biopsy cores, presence of prostatitis and high-grade prostatic intraepithelial neoplasia was analyzed. We also conducted a secondary analysis of the factors that influence upgrading in patients with preoperative Gleason score ≤6 (group 1) and downgrading in patients with Gleason score ≤7 (group 2).
Results:
No difference in Gleason score was noted in 44.3% of patients, while a downgrade was noted in 13.7% and upgrade in 42.1%. About 2/3 of patients with a Gleason score of ≤6 upgraded after radical prostatectomy. PSA density (p = 0.008) and prostate volume (p = 0.032) were significantly correlated with upgrade. No significant predictors were found for patients with Gleason score ≤7 who downgraded postoperatively.
Conclusion:
Smaller prostate volume and higher values of PSA density are predictors for upgrade in patients with biopsy Gleason score ≤6 and this should be considered when deferred treatment modalities are planned.
doi:10.5489/cuaj.270
PMCID: PMC3650813  PMID: 23671515
11.  Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy 
BJU international  2012;110(8):1122-1128.
OBJECTIVE
To investigate preoperative characteristics that distinguish favourable and unfavourable pathological and clinical outcomes in men with high biopsy Gleason sum (8 – 10) prostate cancer to better select men who will most benefit from radical prostatectomy (RP).
PATIENTS AND METHODS
The Institutional Review Board-approved institutional RP database (1982 – 2010) was analysed for men with high-Gleason prostate cancer on biopsy; 842 men were identified.
The 10-year biochemical-free (BFS), metastasis-free (MFS) and prostate cancer-specific survival (CSS) were calculated using the Kaplan – Meier method to verify favourable pathology as men with Gleason <8 at RP or ≤ pT3a compared with men with unfavourable pathology with Gleason 8 – 10 and pT3b or N1.
Preoperative characteristics were compared using appropriate comparative tests.
Logistic regression determined preoperative predictors of unfavourable pathology.
RESULTS
There was favourable pathology in 656 (77.9%) men. The 10-year BFS, MFS and CSS were 31.0%, 60.9% and 74.8%, respectively.
In contrast, men with unfavourable pathological findings had significantly worse 10-year BFS, MFS and CSS, at 4.3%, 29.1% and 52.3%, respectively (all P < 0.001).
In multivariable logistic regression, a prostate-specific antigen (PSA) concentration of > 10 ng/mL (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.38 – 3.62, P = 0.001), advanced clinical stage (≥ cT2b; OR 2.55, 95% CI 1.55 – 4.21, P < 0.001), Gleason pattern 9 or 10 at biopsy (OR 2.55, 95% CI 1.59 – 4.09, P < 0.001), increasing number of cores positive with high-grade cancer (OR 1.16, 95% CI 1.01 – 1.34, P = 0.04) and > 50% positive core involvement (OR 2.25, 95% CI 1.17 – 4.35, P = 0.015) were predictive of unfavourable pathology.
CONCLUSIONS
Men with high-Gleason sum at biopsy are at high risk for biochemical recurrence, metastasis and death after RP; men with high Gleason sum and advanced pathological stage (pT3b or N1) have the worst prognosis.
Among men with high-Gleason sum at biopsy, a PSA concentration of > 10 ng/mL, clinical stage ≥ T2b, Gleason pattern 9 or 10, increasing number of cores with high-grade cancer and > 50% core involvement are predictive of unfavourable pathology.
doi:10.1111/j.1464-410X.2012.10986.x
PMCID: PMC4124597  PMID: 22373045
prostate cancer; high-risk; Gleason sum; outcomes
12.  PTEN Loss is Associated with Upgrading of Prostate Cancer from Biopsy to Radical Prostatectomy 
When distinguishing between indolent and potentially harmful prostate cancers, the Gleason score is the most important variable, but may be inaccurate in biopsies due to tumor under-sampling. This study investigated whether a molecular feature, PTEN protein loss, could help identify which Gleason score 6 tumors on needle biopsy are likely to be upgraded at radical prostatectomy. 71 patients with Gleason score 6 tumors on biopsy upgraded to Gleason score 7 or higher cancer at prostatectomy (cases) were compared to 103 patients with Gleason score 6 on both biopsy and prostatectomy (controls). A validated immunohistochemical assay for PTEN was performed, followed by fluorescence in situ hybridization (FISH) to detect PTEN gene deletion in a subset. PTEN protein loss and clinical-pathologic variables were assessed by logistic regression. Upgraded patients were older than controls (61.8 vs. 59.3 years), had higher pre-operative PSA levels (6.5 vs. 5.3 ng/mL), and a higher fraction of involved cores (0.42 vs. 0.36). PTEN loss by immunohistochemistry was found in 18% (13/71) of upgraded cases compared to 7% (7/103) of controls (p=0.02). Comparison between PTEN immunohistochemistry and PTEN FISH showed the assays were highly concordant, with 97% (65/67) of evaluated biopsies with intact PTEN protein lacking PTEN gene deletion, and 81% (13/16) of the biopsies with PTEN protein loss showing homozygous PTEN gene deletion. Tumors with PTEN protein loss were more likely to be upgraded at radical prostatectomy than those without loss, even after adjusting for age, preoperative PSA, clinical stage and race (odds ratio = 3.04 [1.08–8.55; p=0.035]). PTEN loss in Gleason score 6 biopsies identifies a subset of prostate tumors at increased risk of upgrading at radical prostatectomy. These data provide evidence that a genetic event can improve Gleason score accuracy and highlight a path towards the clinical use of molecular markers to augment pathologic grading.
doi:10.1038/modpathol.2014.85
PMCID: PMC4282985  PMID: 24993522
Prostatic adenocarcinoma; PTEN; upgrading; radical prostatectomy; biopsy
13.  Long-Term Survival after Radical Prostatectomy for men with High Gleason Sum in the Pathological Specimen 
Urology  2010;76(3):715-721.
Objective
To evaluate long-term outcomes of patients with high Gleason sum (8–10) at radical prostatectomy (RP) and to identify predictors of prostate cancer-specific survival (CSS) in this cohort.
Methods
The Institutional RP Database was queried. 9,381 patients with complete follow-up underwent RP from 1982 to 2008; 1,061 patients had pathologic Gleason sum 8–10. Patient and prostate cancer characteristics were evaluated. Survival analyses were performed using Kaplan-Meier method. Univariate and multivariate proportional hazard regression models were created to evaluate pertinent predictors of CSS (death from or attributed to prostate cancer).
Results
Median pre-operative PSA was 7.6 ng/mL; 435 men had clinical stage T1 tumor, 568 had T2, and 36 had T3. Biopsy Gleason sum was <7, =7 and >7 in 244 (22.3%), 406 (37.2%) and 425 (38.9%) patients, respectively. Median follow-up was five years (range 1–23 years). Actuarial 15-year recurrence-free survival, CSS and overall survival rates were 20.7%, 57.4% and 45.4%, respectively. In multivariate analysis, predictors of poor CSS were pathological Gleason sum of 9–10, seminal vesicle and lymph node involvement. Patients with pathological Gleason sum 8 and organ confined disease experienced a CSS of 89.9% at 15 years.
Conclusions
80% of men with Gleason sum 8–10 who undergo RP will experience biochemical recurrence at 15 years. However, CSS approached 90% in men with pathologic organ-confined disease. Higher pathological Gleason sum (9–10), seminal vesicle and lymph node involvement are independent predictors of worse CSS.
doi:10.1016/j.urology.2009.11.085
PMCID: PMC2897964  PMID: 20350749
Prostate cancer; High-Risk; Gleason sum
14.  Upgrading and upstaging in prostate cancer: From prostate biopsy to radical prostatectomy 
Molecular and Clinical Oncology  2014;2(6):1145-1149.
Prostate cancer (CaP) is the most common malignancy in men and the second cause of cancer-related mortality after lung cancer. Several studies have evaluated the correlation between bioptic and pathological Gleason score (GS), documenting a correlation ranging between 30 and 60%. The aim of this study was the evaluation of the association between bioptic and pathological GS in a series of patients undergoing prostate needle biopsy and subsequent radical prostatectomy. We also aimed to evaluate the possible prognostic factors of upgrading and upstaging. We prospectively collected and retrospectively reviewed data from 300 consecutive patients who underwent radical retropubic or robot-assisted prostatectomy at our Institution. Patients who underwent prostate needle biopsy, transrectal or transperineal, with a minimum of 5 samples, were included in this study. Upgrading and downgrading were defined as increase or decrease, respectively, from one prognostic grade group to another, similar to up- or downstaging. The mean age of the patients was 62.97 years and the mean prostate-spesific antigen (PSA) level was 7.83 ng/ml. A total of 51.3% of the population underwent a transperineal prostate biopsy. The most frequently represented bioptic GS was 3+3 (64.0%) followed by 3+4=7 (15.6%); the most frequent pathological Gleason score was 3+4 (44.3%), followed by 3+3 (31.0%). With reagard to the bioptic GS 4-5-6 group, approximately half of the specimens (46.7%) were subsequently upgraded to GS 3+4, and 5.3% to 4+3. With regards to the bioptic GS 3+4 group, 57.4% was confirmed in the surgical specimen. In the 4+3 group, 23.5% of the cases was downgraded to 3+4 and 35.3% was confirmed. With regards to stage, ~39.7% of the patients received an upstaging on the pathological specimen. We evaluated the correlations between preoperative serum PSA level, prostate volume, digital rectal examination and biopsy type and none of the variables considered exhibited a correlation with any upgrading (P>0.05). Moreover, we evaluated the correlations between the aforementioned variables and upstaging and, at the multivariate analysis, only a serum PSA <4 ng/ml was found to be an independent variable predictive of upstaging (P=0.017). Therefore, new tools are required to predict upgrading and upstaging of our patients, in order to ensure better counseling for optimal treatment planning.
doi:10.3892/mco.2014.370
PMCID: PMC4179778  PMID: 25279213
prostate cancer; prostate biopsy; radical prostatectomy; upgrading; upstaging
15.  Risk Stratification of Men with Gleason 7–10 tumors by Primary and Secondary Gleason Score: Results from the SEARCH Database 
Urology  2007;70(2):277-282.
Introduction
Gleason 4+3 prostate cancer is associated with worse clinicopathologic outcomes than Gleason 3+4. Whether the increased risk associated with Gleason 4+3 is equivalent to ≥4+4 is unclear.
Methods
We reviewed data from two separate cohorts pulled from the SEARCH Database. The first consisted of 374 men with biopsy Gleason 3+4 or greater, and the second consisted of 636 men with RP Gleason 3+4 or greater. We estimated the odds ratio of unfavorable surgical pathology for biopsy Gleason categories using logistic regression analysis. Using a Cox proportional hazards regression model, we estimated the relative risk of biochemical progression associated with each biopsy and RP Gleason category.
Results
In the biopsy Gleason cohort, Gleason 4+3 was associated with increased odds of extracapsular extension (p=0.01) and seminal vesicle invasion (p<0.001) relative to biopsy Gleason 3+4. Biopsy Gleason 4+3 was associated with similar odds of adverse pathology relative to biopsy Gleason ≥4+4 (all p values >0.10), except higher-grade pathological tumors among men with biopsy Gleason ≥4+4 (p=0.001). After adjusting for multiple clinical characteristics, biopsy Gleason 4+3 was associated with increased recurrence risk relative to 3+4 (p=0.001), but similar progression risk as biopsy Gleason ≥4+4 (p=0.53). In the RP Gleason cohort and after adjustment for multiple clinicopathologic features, RP Gleason 4+3 was associated with increased progression risk relative to RP Gleason 3+4 (p=0.03), but similar progression risk as RP Gleason ≥4+4 (p= 0.24).
Conclusions
In a multicenter database using pooled data from multiple pathologists, Gleason scores 4+3 and ≥4+4 exhibited similar clinicopathologic outcomes.
doi:10.1016/j.urology.2007.03.059
PMCID: PMC3275808  PMID: 17826489
Prostate cancer; radical prostatectomy; Gleason; prostate biopsy; progression
16.  Long-term outcome among men with conservatively treated localised prostate cancer 
British Journal of Cancer  2006;95(9):1186-1194.
Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10–30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients.
doi:10.1038/sj.bjc.6603411
PMCID: PMC2360576  PMID: 17077805
localised prostate cancer; prognostic factors
17.  Factors effective on survival after radical prostatectomy: To what extent is pre-operative biopsy Gleason scoring is confident in predicting the prognosis? 
Urology Annals  2015;7(2):159-165.
In the present study, the effect of different grades on independent survival from the biochemical relapse was investigated through comparison of the histological grades of the biopsy and prostatectomy materials in patients undergoing radical prostatectomy (RP). A total of 152 patients undergoing RP following biopsy were retrospectively investigated in an attempt to reveal the effect of discordance between needle biopsy Gleason score and RP Gleason score on prostate specific antigen relapse-free survival. Accordingly, while 58.3% (14/24) survival was seen in the patients in Group 1 (high-graded) with Gleason score 7, 93.7% (15/16) survival has been seen in the patients in Group 2 (low-graded) and Group 3 (same Gleason scores) with Gleason score 7. The difference in-between has been statically found significant (P < 0.001). Similarly, while a 10% (1/10) survival is seen in the patients in Group 1 with Gleason score 8 and above, 75% (3/4) survival has been observed in the patients in Group 2 and 3 with Gleason score 8 and above. Also in this comparison, the difference in-between has been statically found significant (P = 0.041). Eventually, different grading, particularly determination of Gleason score higher than the RP specimen biopsy also bring about bad pathologic parameters and shortened survival periods.
doi:10.4103/0974-7796.150527
PMCID: PMC4374252  PMID: 25837974
Gleason score; prostate carcinoma; radical prostatectomy; upgrading
18.  Operator Dependent Choice of Prostate Cancer Biopsy Has Limited Impact on a Gene Signature Analysis for the Highly Expressed Genes IGFBP3 and F3 in Prostate Cancer Epithelial Cells 
PLoS ONE  2014;9(10):e109610.
Background
Predicting the prognosis of prostate cancer disease through gene expression analysis is receiving increasing interest. In many cases, such analyses are based on formalin-fixed, paraffin embedded (FFPE) core needle biopsy material on which Gleason grading for diagnosis has been conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator's choice of biopsy was evaluated.
Methods
Multiple biopsy samples from 43 patients were evaluated using a previously reported gene signature of IGFBP3, F3 and VGLL3 with potential prognostic value in estimating overall survival at diagnosis of prostate cancer. A four multiplex one-step qRT-PCR test kit, designed and optimized for measuring the signature in FFPE core needle biopsy samples was used. Concordance of gene expression levels between primary and secondary Gleason tumor patterns, as well as benign tissue specimens, was analyzed.
Results
The gene expression levels of IGFBP3 and F3 in prostate cancer epithelial cell-containing tissue representing the primary and secondary Gleason patterns were high and consistent, while the low expressed VGLL3 showed more variation in its expression levels.
Conclusion
The assessment of IGFBP3 and F3 gene expression levels in prostate cancer tissue is independent of Gleason patterns, meaning that the impact of operator's choice of biopsy is low.
doi:10.1371/journal.pone.0109610
PMCID: PMC4190108  PMID: 25296164
19.  Outcomes of Gleason Score ≤8 among High Risk Prostate Cancer Treated with 125I Low Dose Rate Brachytherapy Based Multimodal Therapy 
Yonsei Medical Journal  2013;54(5):1207-1213.
Purpose
To investigate the role of low dose rate (LDR) brachytherapy-based multimodal therapy in high-risk prostate cancer (PCa) and analyze its optimal indications.
Materials and Methods
We reviewed the records of 50 high-risk PCa patients [clinical stage ≥T2c, prostate-specific antigen (PSA) >20 ng/mL, or biopsy Gleason score ≥8] who had undergone 125I LDR brachytherapy since April 2007. We excluded those with a follow-up period <3 years. Biochemical recurrence (BCR) followed the Phoenix definition. BCR-free survival rates were compared between the patients with Gleason score ≥9 and Gleason score ≤8.
Results
The mean initial PSA was 22.1 ng/mL, and mean D90 was 244.3 Gy. During a median follow-up of 39.2 months, biochemical control was obtained in 72% (36/50) of the total patients; The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores ≤8, and 40% for those with Gleason scores ≥9 (p<0.001). In Cox multivariate analysis, only Gleason score ≥9 was observed to be significantly associated with BCR (p=0.021). Acute and late grade ≥3 toxicities were observed in 20% (10/50) and 36% (18/50) patients, respectively.
Conclusion
Our results showed that 125I LDR brachytherapy-based multimodal therapy in high-risk PCa produced encouraging relatively long-term results among the Asian population, especially in patients with Gleason score ≤8. Despite small number of subjects, biopsy Gleason score ≥9 was a significant predictor of BCR among high risk PCa patients after brachytherapy.
doi:10.3349/ymj.2013.54.5.1207
PMCID: PMC3743192  PMID: 23918571
Prostate cancer; brachytherapy; high risk group; biochemical recurrence
20.  Maximum tumor diameter is not an independent prognostic factor in high-risk localized prostate cancer 
World Journal of Urology  2008;26(3):237-241.
Objectives
Previous studies suggest that maximum tumor diameter (MTD) is a predictor of recurrence in prostate cancer (PC). This study investigates the prognostic value of MTD for biochemical recurrence (BCR) in patients with PC, after radical prostatectomy (RP), with emphasis on high-risk localized prostate cancer.
Methods
RP specimens of 542 patients were evaluated with a median follow-up of 39.5 months (range 0.6–150 months). MTD was defined as the largest diameter of the largest tumor; high-risk as ≥T2c or PSA level > 20 ng/ml or Gleason score ≥8 and BCR as two consecutive PSA levels > 0.10 ng/ml. Proportional hazards multivariable regression models were composed to determine prognostic factors for BCR.
Results
Overall, 114 patients developed BCR after RP. The overall 5-year risk of BCR was 25% (95% CI = 20.4–29.6), and median MTD was 24 mm (range 1–65). MTD in the total and high-risk group was associated with total tumor volume, volume of the largest tumor, pre-operative PSA levels, and Gleason score. In a univariable analyses, MTD was weakly associated with risk of BCR (HR = 1.02 per mm increase, 95% CI = 1.002–1.035, P = 0.024) in the total group; in the high-risk group this association was lost (HR = 1.01, 95%CI = 0.99–1.03, P = 0.18). Multivariable analyses indicated that positive surgical margins, higher Gleason score, advanced pathological stage, and multiple tumors were the main prognostic factors for BCR irrespective of the risk profile. MTD did not provide additional information.
Conclusions
MTD is not an independent prognostic factor for BCR in patients treated with RP, irrespective of the risk profile.
doi:10.1007/s00345-008-0242-7
PMCID: PMC2413091  PMID: 18265988
Prostate; Prostatectomy; Prognosis; Localized; High risk
21.  Pathological correlation between needle biopsy and radical prostatectomy specimen in patients with localized prostate cancer 
Objective
This study aims to evaluate the accuracy of transrectal ultrasound (TRUS) guided prostate biopsies in predicting pathological grading and tumour distribution in the final pathological specimen of patients who underwent radical prostatectomy for clinically localized prostate cancer. The study ultimately aims to gain more understanding of the pathological behaviour of prostate cancer and the limitations of the currently available diagnostic and prognostic tools.
Material and Methods
We reviewed the records of 100 patients with localized carcinoma of the prostate diagnosed by TRUS-guided prostate biopsy and treated with radical retropubic prostatectomy, comparing tumour laterality and Gleason score in core biopsies with tumour distribution and Gleason score of the surgical specimen. We then correlated both results to diagnostic and prognostic variables such as prostate specific antigen (PSA) values and surgical margins.
Results
All 44 patients with bilateral disease on needle biopsy had bilateral disease on final pathology, with 15 of these patients (34%) having positive margins. Of the 56 patients with unilateral disease on biopsy, 37 (66%) had bilateral disease on final pathology; however, only 4 of them (7%) had positive margins (p < 0.001). Median Gleason score on final pathology was upgraded to 7, compared with a median score of 6 on biopsies. Stratifying patients to 2 groups based on their PSA level (group 1: PSA < 10 ng/mL, 72 patients; group 2: PSA > 10ng/mL, 28 patients), revealed that 57 patients (79%) in group 1 and 24 patients (85%) in group 2 had bilateral disease. In addition, 13 patients (18%) in group 1 and 6 patients (21%) in group 2 had positive margins.
Conclusions
Sixty-six percent of patients with unilateral disease on needle biopsy had bilateral disease on final pathology, but this does not increase their rate of having positive margins. Gleason score is upgraded from 6 to 7. PSA did not seem to affect laterality of disease in patients selected for radical prostatectomy.
PMCID: PMC2422971  PMID: 18542801
22.  Oncological and functional results of extraperitoneal laparoscopic radical prostatectomy 
Oncology Letters  2012;4(2):351-357.
The oncological and functional results of 329 cases in a population treated with extraperitoneal laparoscopic radical prostatectomy (ELRP) were evaluated retrospectively. A total of 329 inconsecutive patients with prostate cancer (PCa) who underwent ELRP were retrospectively analyzed. The median initial prostate-specific antigen (PSA) level was 17.35 ng/ml. The median biopsy Gleason score was 7.77. Patients with a T2 or T3a clinical stage had received preoperative neoadjuvant hormonal therapy (NHT) for 3 to 9 months prior to ELRP. No conversion or re-intervention were observed. The median time for anastomosis, surgery time and postoperative catheterization time were 13.0 min, 90.0 min and 6 days, respectively. The median estimated blood loss was 75 ml. There were 12 temporary urinary leakages requiring prolonged catheterization to 14 days. There was 1 case of deep vein thrombosis, 1 case of alimentary tract hemorrhage and 7 cases of anterior urethral stricture. The median follow-up time was 27 months. A total of 17 patients were lost during the follow-up period. No rectal injury, lymphocele, incision hernia, postoperative persistent urinary leak or anastomotic stricture occurred. Younger patients (≤67 years of age) had a more rapid recovery of continence and a better postoperative potency. The overall positive surgical margin rate was 16.7%, which correlated with the pathological stage and Gleason score, respectively (both P<0.001). A total of 89 (28.6%) patients were diagnosed with biochemical recurrence. The initial PSA value, PSM, pathological stage and Gleason score were identified as independent prognostic factors for biochemical recurrence-free survival using multivariate analysis. Our results demonstrated that preoperative NHT had significant effects on the pathological Gleason score (P<0.001) and surgical margin (P=0.027), but no significant impact on biochemical recurrence (P=0.202). The reproducibility of ELRP has been proven as a reliable curative treatment in Western countries during the last 15 years. Due to the increase in PCa patients, the results of our study may aid surgeons who use ELRP for the first time.
doi:10.3892/ol.2012.737
PMCID: PMC3402759  PMID: 22844382
prostate cancer; laparoscopic radical prostatectomy; follow-up; continence; potency; biochemical recurrence
23.  Prostate cancer: Relationship between vascular diameter, shape and density and Gleason score in needle biopsy specimens 
Background:
Tumor growth requires expansion and development of vascular network. An increase in Gleason score is representative of an increase in tumor invasion and extent. In this study, the relationship between Gleason score and vascular characteristics of needle biopsy samples in prostate cancer patients has been evaluated.
Materials and Methods:
We evaluated vascular characteristics including density and size of vessels; and percentage of vessels with irregular shape in 62 cancer-positive samples obtained by prostate needle biopsy under ultrasound guide, and compared them to Gleason score.
Result:
Gleason scores of 23 patients were ≤6; Gleason scores of 18 patients were 7 and 21 patients had their Gleason score from 8 to 10. An increase in Gleason score was associated with increased vascular density (P < 0.0001), increased percentage of vessels with irregular shape (P < 0.02) and decreased average vascular diameter (P < 0.015), from which the relationship with vascular density was clearer and more evident.
Conclusion:
Vascular morphological characteristics can be representative of angiogenic potential of prostate cancer which is required for tumor progression. As Gleason score can prognosticate the behavioral characteristics of prostate cancer in future, vascular characteristics may also be able to express tumor behavior. With attention to vascular characteristics in biopsy samples and apart from Gleason score, we may also be able to divide patients into other subtypes in a way being helpful for the establishment of treatment plan.
doi:10.4103/2277-9175.107963
PMCID: PMC3732884  PMID: 23930248
Gleason score; prostate cancer; vessel density
24.  Intensity of stromal changes is associated with tumor relapse in clinically advanced prostate cancer after castration therapy 
Asian Journal of Andrology  2014;16(5):710-714.
Reactive stromal changes in prostate cancer (PCa) are likely involved in the emergence of castration-resistant PCa (CRPC). This study was designed to investigate stromal changes in patients with clinically advanced PCa and analyze their prognostic significance. Prostate needle biopsies obtained from 148 patients before castration therapy were analyzed by Masson trichrome staining and immunohistochemical analysis of vimentin and desmin. Reactive stroma grading was inversely correlated with Gleason score. Stroma grade (Masson stain 82.8% vs 45.6%, P < 0.001) and vimentin expression (P = 0.005) were significantly higher, and desmin expression (P = 0.004) significantly lower, in reactive stroma of tumors with a Gleason score of 6–7 than in adjacent peritumoral tissue. Kaplan-Meier analysis showed a significant association between reactive stroma grade in tumors and the occurrence of CRPC in patients with a Gleason score of 6–7 (P = 0.009). Furthermore, patients with higher vimentin or lower desmin expression had a shorter disease-free period. In multivariate analysis, only vimentin expression was a significant predictor of tumor relapse (hazard ratio 1.78, 95% confidence interval 1.12–10.26, P = 0.012). These findings indicate that the intensity of reactive stroma is associated with castration responsiveness, especially in patients with a lower Gleason score where the abundant stroma component is most frequently found. High expression of vimentin in tumor stroma was independently associated with poor outcomes in patients with Gleason scores of 6–7, and may serve as a new prognostic marker in daily practice.
doi:10.4103/1008-682X.129131
PMCID: PMC4215666  PMID: 24875819
cancer-associated fibroblasts; castration resistance; prostate cancer; reactive stroma; vimentin
25.  Up-to-date results of carbon-ion radiotherapy for prostate cancer 
Journal of Radiation Research  2014;55(Suppl 1):i28-i29.
Carbon ion radiotherapy (C-ion RT) for prostate cancer was started in 1995 using the Heavy-Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS), Japan. After preceding phase I/II dose-escalation studies of 20 fractions over 5 weeks, a phase II study was initiated in April 2000 using the treatment techniques and the recommended dose fractionations established by the phase I/II studies. This study was also successfully completed in October 2003 when the C-ion RT for solid tumors, including the prostate cancer, was approved as ‘Advanced Medicine’ by the Ministry of Health, Labor, and Welfare. Since then, more than 1400 patients have been treated with C-ion RT as of February 2012, and advancement of hypofractionation has also been achieved. In this paper, the treatment outcomes in 1144 patients who underwent the established C-ion RT between April 2000 and July 2012 were analyzed.
Out of 1144 patients, 585 patients were categorized as high-risk group, which includes patients having at least one of the following conditions: T3 clinical stage, Gleason's score of 8 or higher and PSA of 20 or higher. One hundred and ninety-seven patients who met the conditions such as clinical stage of T2a or lower, Gleason's score of 6 or lower and PSA of <20 were categorized as low-risk group. Three hundred and sixty-two patients who were not included in either high- or low-risk group were categorized as intermediate-risk group. All patients were pathologically proven to have adenocarcinoma of the prostate, and Gleason's score was determined by the chief pathologist of our study group. Written consent was obtained from all patients included in the clinical study. Patients with the following conditions were not registered in the clinical trial: having distant metastases, having synchronous primary malignancy, not histologically proven cancer, without informed consent, post-operative/post-irradiation recurrence.
All patients were treated with three field irradiations (vertical one field and horizontal opposing two fields). The prostate and proximal part of the seminal vesicle were contoured as clinical target volume (CTV), and planning target volume (PTV) was set with 5–10 mm margins around the CTV. On the way of radiotherapy, a part of irradiation field of the posterior side was cut to reduce the rectal dose. The 197 patients in the low-risk group did not undergo androgen deprivation therapy (ADT), whereas the 947 patients of intermediate- and high-risk groups underwent ADT. The patients of intermediate-risk group underwent about 6 months of neoadjuvant ADT, and the patients of high-risk group also underwent about 6 months of neoadjuvant ADT and sequential adjuvant ADT for more than 18 months. The median age of all patients was 68 years, and the median follow-up time was 48.7 months (range: 3.6–151.1 months).
The 5-year overall survival rate and biochemical relapse-free rate of the entire groups was 95.7% and 91.0%, respectively. T-stage and Gleason's score were significant prognostic factors for both the biochemical control and patient survival and initial PSA was also a predictive factor for survival. Regarding the late radiation toxicity, the incidence of rectal toxicity of grade 2 or worse was 1.1% and that of genitourinary toxicity was 6.5%. These outcomes seemed to be better than those of the past publications [ 1– 4]. In addition, the incidence of toxicity in patients treated with more hypofractionated C-ion RT of 16 fractions over 4 weeks was lower than those of 20 fraction treatment. These favorable outcomes can be thought as apparent evidence of physical and biological advantages of the hypofractionated C-ion RT.
doi:10.1093/jrr/rrt177
PMCID: PMC3941550
carbon-ion radiation therapy; prostate cancer; hypofractionation

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