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.
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.
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.
The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy.
Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer.
In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10−9) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10−5), with Gleason score (P=5 × 10−4) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions.
For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.
localised prostate cancer; prognostic factors; cell cycle genes; expression profiles; CCP score; needle biopsy
In men who are at high-risk of prostate cancer, progression and death from cancer after radical retropubic prostatectomy (RRP), limited prognostic information is provided by established prognostic features. The objective of this study was to develop a model predictive of outcome in this group of patients.
Candidate genes were identified from microarray expression data from 102 laser capture microdissected prostate tissue samples. Candidates were overexpressed in tumor compared with normal prostate and more frequently in Gleason patterns 4 and 5 than in 3. A case control study of 157 high-risk patients, matched on Gleason score and stage with systemic progression or death of prostate cancer as the end point, was used to evaluate the expression of candidate genes and build a multivariate model. Tumor was collected from the highest Gleason score in paraffin-embedded blocks and the gene expression was quantified by real-time reverse transcription polymerase chain reaction. Validation of the final model was performed on a separate case-control study of 57 high-risk patients who underwent RRP.
A model incorporating gene expression of topoisomerase-2a, cadherin-10, the fusion status based on ERG, ETV1, and ETV4 expression, and the aneuploidy status resulted in a 0.81 area under the curve (AUC) in receiver operating characteristic statistical analysis for the identification of men with systemic progression and death from high grade prostate cancer. The AUC was 0.79 in the independent validation study.
The model can identify men with high-risk prostate cancer who may benefit from more intensive postoperative follow-up and adjuvant therapies.
To determine if PNI should be included in addition to PSA, biopsy Gleason score, and clinical T-stage for risk-stratification of patients with localized prostate cancer.
Methods and Materials
We analyzed prostatectomy findings for 1550 patients, from a prospectively collected institutional database, to determine whether PNI was a significant predictor for upgrading of Gleason score or pathologic T3 disease after patients were stratified into low-, intermediate-, and high-risk groups (on the basis of PSA, biopsy Gleason score, and clinical T-stage).
For the overall population, PNI was associated with a significantly increased frequency of upgrading and of pathologic T3 disease. After stratification, PNI was still associated with significantly increased odds of pathologic T3 disease within each risk group. In particular, for low-risk patients, there was a markedly increased risk of extraprostatic extension (23% vs 7%), comparable to that of intermediate-risk patients. Among high-risk patients, PNI was associated with an increased risk of seminal vesicle invasion and lymph node involvement. Furthermore, over 80% of high-risk patients with PNI were noted to have an indication for post-operative radiation.
PNI may be useful for risk-stratification of prostate cancer. Our data suggest that low-risk patients with PNI on biopsy may benefit from treatment typically reserved for those with intermediate-risk disease. In addition, men with high-risk disease and PNI, who are contemplating surgery, should be informed of the high likelihood of having an indication for postoperative radiation therapy.
Perineural invasion; Prostate cancer; Risk stratification; Gleason score; Pathologic stage
Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models.
We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases.
Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors.
The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.
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.
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.
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.
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.
Prostate cancer; radical prostatectomy; Gleason; prostate biopsy; obesity
To evaluate the influence of the maximum involvement of biopsy core (MIBC) on outcome for prostate cancer patients treated with dose-escalated external beam radiotherapy (EBRT).
Methods and materials
The outcomes of 590 men with localized prostate cancer treated with EBRT (≥75 Gy) at a single institution were retrospectively analyzed. The influence of MIBC on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) was compared to other surrogates for biopsy tumor volume, including the percentage of positive biopsy cores (PPC) and the total percentage of cancer volume (PCV).
MIBC correlated with PSA, T-stage, Gleason score, NCCN risk group, PPC, PCV, and treatment related factors. On univariate analysis, MIBC was prognostic for all endpoints except OS; with greatest impact in those with Gleason scores of 8–10. However, on multivariate analysis, MIBC was only prognostic for FFBF (hazard ratio [HR] 1.9, p = 0.008), but not for FFM (p = 0.19), CSS (p = 0.16), and OS (p = 0.99).
In patients undergoing dose-escalated EBRT, MIBC had the greatest influence in those with Gleason scores of 8–10 but provided no additional prognostic data as compared to PPC and PCV, which remain the preferable prognostic variables in this patient population.
Prostate cancer; Biopsy; prognostic factors; Maximum involvement; Tumor in Core; Radiotherapy
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.
The survival of 117 patients with carcinoma of the prostate treated with radiation at SUNY-Health Science Center at Brooklyn and Kings County Hospital Center was analyzed according to their pretreatment method of diagnosis. Sixty-four patients (54.7%) underwent a transurethral resection of the prostate (TURP) for obstructive symptoms prior to definitive therapy, while 53 patients (45.3%) were diagnosed with needle biopsy. The overall 5-year survival rate was 46% in the needle biopsy group and 38% in the TURP group. Black and white patients with high Gleason scores (7 to 10) and black patients with low-grade tumors who underwent TURP had an adverse 5-year survival rate compared with those patients diagnosed by needle biopsy. The 5-year survival rate of patients with high Gleason scores comparing needle and TURP was 37% versus 16%. The 5-year survival rate of black patients with low-grade tumors comparing needle biopsy versus TURP was 50% and 22%, respectively, although not statistically significant because of the small sample size. When evaluated by stage, there was no difference in survival rates of TURP versus needle biopsy. Black patients who underwent TURP had a 28% 5-year survival rate compared with a 44% 5-year survival rate in white TURP patients. This analysis reveals that black and white patients with high-grade tumors and black patients, even with low-grade tumors, may have a lower survival rate if they undergo TURP prior to radiation, but this may be due to higher stage and larger volume disease in these patients.
Prostate cancer is the most commonly diagnosed cancer in men and the second leading cause of cancer death in men. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and there are many studies recently done, showing that prostate cancer growth is also influenced by estrogen. The characterization of estrogen receptor beta (ER-b) brought new insight into the mechanisms underlying estrogen signalling. In the present study, we investigated the expression of estrogen receptor-b (ER-b) in human prostate cancer tissues.
We selected 52 paraffin-embedded blocks of prostate needle biopsies in a cross-sectional study to determine frequency and rate of ER-b expression in different grades of prostate adenocarcinoma according to Gleason grading system. Immunohistochemical staining of tissue sections by monoclonal anti ER-b antibody was performed using an Envision method visualising system.
ER-b expression was seen in tumoral cells of prostatic carcinoma in all 29 cases with low and intermediate tumors (100%) and 19 of 23 cases with high grade tumor (83%). Mean rate of ER-b expression in low & intermediate grade cancers was 68.41% (SD = 25.63) whereas high grade cancers showed 49.48% rate of expression (SD = 28.79).
ER-b expression is reduced in high grade prostate cancers compared to low & intermediate grade ones (P value 0.027).
Few biomarkers are available to predict prostate cancer risk. Single nucleotide polymorphisms (SNPs) tend to have weak individual effects but, in combination, they have stronger predictive value. Adipokine pathways have been implicated in the pathogenesis. We used a candidate pathway approach to investigate 29 functional SNPs in key genes from relevant adipokine pathways in a sample of 1006 men eligible for prostate biopsy. We used stepwise multivariate logistic regression and bootstrapping to develop a multilocus genetic risk score by weighting each risk SNP empirically based on its association with disease. Seven common functional polymorphisms were associated with overall and high-grade prostate cancer (Gleason≥7), whereas three variants were associated with high metastatic-risk prostate cancer (PSA≥20 ng/mL and/or Gleason≥8). The addition of genetic variants to age and PSA improved the predictive accuracy for overall and high-grade prostate cancer, using either the area under the receiver-operating characteristics curves (P<0.02), the net reclassification improvement (P<0.001) and integrated discrimination improvement (P<0.001) measures. These results suggest that functional polymorphisms in adipokine pathways may act individually and cumulatively to affect risk and severity of prostate cancer, supporting the influence of adipokine pathways in the pathogenesis of prostate cancer. Use of such adipokine multilocus genetic risk score can enhance the predictive value of PSA and age in estimating absolute risk, which supports further evaluation of its clinical significance.
Treatment decisions after diagnosis of clinically localised prostate cancer are difficult due to variability in tumour behaviour. We therefore examined one of the most promising biomarkers in prostate cancer, Ki-67, in a cohort of 808 patients diagnosed with prostate cancer between 1990 and 1996 and treated conservatively. Ki-67 expression was assessed immunohistochemically, in two laboratories, by two different scoring methods and the results compared with cancer-specific and overall survival. The power of the biomarker was compared with Gleason score and initial serum prostate-specific antigen (PSA). Both methods showed that Ki-67 provided additional prognostic information beyond that available from Gleason score and PSA: for the semi-quantitative method, Δχ2 (1 d.f.)=24.6 (P<0.0001), overall survival χ2=20.5 (P<0.0001), and for the quantitative method, Δχ2 (1 d.f.)=15.1 (P=0.0001), overall survival χ2=10.85 (P=0.001). Ki-67 is a powerful biomarker in localised prostate cancer and adds to a model predicting the need for radical or conservative therapy. As it is already in widespread use in routine pathology, it is confirmed as the most promising biomarker to be applied into routine practice.
prostate cancer; Ki-67; watchful waiting; active surveillance; biomarker
Gleason grading is an important predictor of prostate cancer (PCa) outcomes. Studies using surrogate PCa end points suggest outcomes for Gleason score (GS) 7 cancers vary according to the predominance of pattern 4. These studies have influenced clinical practice, but it is unclear if rates of PCa mortality differ for 3 + 4 and 4 + 3 tumors. Using PCa mortality as the primary end point, we compared outcomes in Gleason 3 + 4 and 4 + 3 cancers, and the predictive ability of GS from a standardized review versus original scoring.
Patients and Methods
Three study pathologists conducted a blinded standardized review of 693 prostatectomy and 119 biopsy specimens to assign primary and secondary Gleason patterns. Tumor specimens were from PCa patients diagnosed between 1984 and 2004 from the Physicians' Health Study and Health Professionals Follow-Up Study. Lethal PCa (n = 53) was defined as development of bony metastases or PCa death. Hazard ratios (HR) were estimated according to original GS and standardized GS. We compared the discrimination of standardized and original grading with C-statistics from models of 10-year survival.
For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared with 3 + 4 cancers (95% CI, 1.1 to 8.6). The discrimination of models of standardized scores from prostatectomy (C-statistic, 0.86) and biopsy (C-statistic, 0.85) were improved compared to models of original scores (prostatectomy C-statistic, 0.82; biopsy C-statistic, 0.72).
Ignoring the predominance of Gleason pattern 4 in GS 7 cancers may conceal important prognostic information. A standardized review of GS can improve prediction of PCa survival.
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.
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.
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.
prostate; prostatic neoplasms; prostatectomy; mortality; biopsy
TMPRSS2-ERG gene rearrangement is seen in about half of clinically-localized prostate cancers, yet controversy exists regarding its prognostic implications. Similarly, the relationship of TMPRSS2-ERG fusion to Gleason score and morphology remains uncertain. We assigned Gleason scores and recorded morphologic features for 521 clinically-localized prostate cancers sampled in triplicate and arrayed in 8 tissue microarray blocks. Fluorescence in situ hybridization was performed to delineate TMPRSS2-ERG aberrations. Using maximum Gleason score, based on 3 core evaluation, and overall Gleason score, based on prostatectomy sections, Fisher’s exact test was performed for tumors with TMPRSS2-ERG translocation/deletion, copy number increase (≥3) of the TMPRSS2-ERG region without translocation/deletion, and copy number increase and concomitant translocation/deletion. 217 (41%) translocation/deletion and 30 (5.9%) copy number increase alone cases were detected. Among 217 translocation/deletion cases, 32 had translocation/deletion with copy number increase. 237, 200, and 75 cancers had maximum core-specific Gleason score of 6, 7, and 8–10, respectively. Tumors with translocation/deletion tended toward lower Gleason scores than those without (p=0.002) with similar results for overall Gleason score (p=0.02); Copy number increase cases tended toward higher Gleason scores than those without (p<0.001). Gleason score 8–10 tumors demonstrated lower odds of translocation/deletion (OR 0.38; 95%CI 0.21–0.68) and higher odds of copy number increase alone (OR 7.33; 95%CI 2.65–20.31) or copy number increase + translocation/deletion (OR 3.03; 95%CI 1.12–8.15) relative to Gleason score < 7 tumors. No significant difference in TMPRSS2-ERG incidence was observed between patients with and without cribriform glands, glomerulations, signet ring cells, or intraductal cancer (p=0.821, 0.095, 0.132, 0.375). TMPRSS2-ERG gene fusion is associated with lower core-specific and overall Gleason scores and not with high grade morphologies. Conversely, TMPRSS2-ERG copy number increase, with or without rearrangement, is associated with higher Gleason score. These findings indicate that translocation/deletion of TMPRSS2-ERG is not associated with histologic features of aggressive prostate cancer.
TMPRSS2; ERG; fusion; prostate cancer; Gleason score; morphology
We examined contralateral prostate cancer potentially left behind by focal therapy.
Materials and Methods
We investigated 100 completely embedded radical prostatectomy specimens in which needle biopsy predicted limited disease (less than 3 positive cores, 50% or less involvement of any positive core, Gleason score 6 or less) and all positive needle cores were unilateral. Clinical stage was T1c in 85 and T2a in 15 cases with the palpable lesion on the positive biopsy side.
There was 1 positive core in 66 cases. On average 13.9% of each positive core was involved with tumor. The mean number of separate tumor nodules per radical prostatectomy was 2.9. In 65 radical prostatectomy specimens there was some tumor contralateral to the positive biopsy side. Total tumor volume in the radical prostatectomy contralateral to the positive biopsy side averaged 0.2 cm3 (largest 1.3). In 23 cases contralateral tumor volume was greater than biopsy positive side tumor volume. There were 13 cases in which more than 0.5 cm3 cancer was contralateral to the positive biopsy and 7 with predominantly anterior tumor. Volume contralateral to positive biopsy side could not be predicted by the number of positive cores (1 vs 2) or maximum percent of the core involved. Gleason pattern 4, extraprostatic extension or positive margins were seen contralateral to the positive biopsy side in 13, 1 and 2 cases, respectively.
In a highly selected population with limited unilateral biopsy cancer, tumor contralateral to the positive biopsy side at radical prostatectomy is typically small. However, 20% of radical prostatectomy specimens had some contralateral adverse pathology in terms of size, extraprostatic extension, grade or margins.
prostatic neoplasms; cryosurgery; prostatectomy
The association of central obesity, hyperinsulinemia, and dyslipidemia with higher grade advanced prostate cancer as determined by Gleason grading is not well understood. We evaluated the effect of central obesity waist hip ratio (WHR ≥ 0.9) and biochemical parameters associated with central obesity on Gleason grading in North Indian patients of prostate cancer presenting at advanced stages.
Materials and Methods:
A cross-sectional study was conducted among 50 nondiabetic patients having clinical stages III and IV prostate cancer. Gleason grading on core biopsy samples by histopathology was done and patients were divided in two groups—group1, Gleason score ≥8; group 2, Gleason score <8. WHR along with serum levels of prostate-specific antigen (PSA), testosterone, insulin, and lipid profile was done in each patient.
The two groups are similar in Age (67.54 years); range (50-80 years). Group 1 men had statistically higher mean WHR (0.96 vs 0.90; P ≤ 0.001), higher mean triglyceride level (201.34 vs 150.52 mg/dL; P=0.0006), higher mean very low-density lipoprotein (VLDL) (40.27 vs 30.10 mg/dL; P =0.0006), higher mean insulin (19.49 vs 15.04 μIU/mL; P = 0.0024), and lower mean high-density lipoprotein (HDL) levels (32.39 vs 36.82 mg/dL; P = 0.034) than men in group 2. Serum levels of cholesterol, LDL, and testosterone did not show statistically significant differences between the two groups.
This pilot study involving small number of patients indicates that central obesity, dyslipidemia, and hyperinsulinemia could be associated with high-grade prostate cancer.
Central obesity; insulin; lipids; prostate cancer
To evaluate the pathologic outcome of prostate-specific antigen-screened patients with high-grade (Gleason score ≥ 8) prostate cancer limited to 1 biopsy core, without clinical evidence of disease.
Ninety-two patients with only 1 biopsy core with cancer and treated by radical prostatectomy were divided into 4 groups according to the biopsy Gleason score: 3 + 3 = 6 (23 cases), 3 + 4 = 7 (25 cases), 4 + 3 = 7 (20 cases), and ≥8 (24 cases).
Cases with Gleason score ≥8 showed a significantly higher proportion of extraprostatic extension (50%), positive surgical margins (21%), and seminal vesicle invasion (12%) when compared with the other groups. Patients with Gleason score ≥8 in the biopsy had a 25-fold increased in the odds ratio for extraprostatic extension in the prostatectomy. The incidence of extraprostatic extension was higher in those with prostatic cancer involving ≥50% of one core (88%) compared with cases involving <50% (32%).
In patients with prostate cancer limited to 1 biopsy core, the presence of Gleason score ≥8 significantly increased the incidence of extraprostatic extension, positive surgical margins, and seminal vesicle invasion. The odds ratio was substantially higher in patients with ≥50% of Gleason ≥8 in the biopsy core. These data might be taken into account for proper clinical management of this set of patients.
Over-diagnosis and treatment of prostate cancer has been a major problem in prostate cancer care and management. Currently the most relevant prognostic factor to predict a patient's risk of death due to prostate cancer is the Gleason score of the biopsied tissue samples. However, pathological analysis is subjective, and the Gleason score is only a qualitative estimate of the cancer malignancy. Molecular biomarkers and diagnostic tests that can accurately predict prostate tumor aggressiveness are rather limited.
We report here for the first time the development of a nanoparticle test that not only can distinguish prostate cancer from normal and benign conditions, but also has the potential to predict the aggressiveness of prostate cancer quantitatively. To conduct the test, a prostate tissue lysate sample is spiked into a blood serum or human IgG solution and the spiked sample is incubated with a citrate-protected gold nanoparticle solution. IgG is known to adsorb to citrate-protected gold nanoparticles to form a "protein corona" on the nanoparticle surface. From this study, we discovered that certain tumor-specific molecules can interact with IgG and change the adsorption behavior of IgG to the gold nanoparticles. This change is reflected in the nanoparticle size of the assay solution and detected by a dynamic light scattering technique. Assay data were analyzed by one-way ANOVA for multiple variant analysis, and using the Student t-test or nonparametric Mann-Whitney U-tests for pairwise analyses.
An inverse, quantitative correlation of the average nanoparticle size of the assay solution with tumor status and histological diagnostic grading was observed from the nanoparticle test. IgG solutions spiked with prostate tumor tissue exhibit significantly smaller nanoparticle size than the solutions spiked with normal and benign tissues. The higher grade the tumor is, the smaller the nanoparticle size is. The test particularly revealed large differences among the intermediate Grade 2 tumors, and suggested the need to treat them differently.
Development of a new nanoparticle test may provide a quantitative measure of the prostate cancer aggressiveness. If validated in a larger study of patients with prostate cancer, this test could become a new diagnostic tool in conjunction with Gleason Score pathology diagnostics to better distinguish aggressive cancer from indolent tumor.
Prostate cancer; Cancer aggressiveness; Biomarker; Nanoparticle; Molecular diagnostics
The molecular mechanism of prostate cancer is poorly understood. The aim of the study was to investigate the prevalence and prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and p16 among benign prostatic hyperplasia (BPH) and prostate cancer patients.
In this case-control study, 63 patients were included in three groups; 21 with BPH as the control group, 21 with prostate cancer and good prognostic factors (based on prostate-specific antigen, Gleason score and stage) as good prognosis group, and 21 with prostate cancer and poor prognostic features as poor prognosis group. The prostate biopsy specimen of each individual was examined for hypermethylation of RARB and p16 promoters by methylation specific PCR (MSPCR).
Seven (33.3%) patients with good prognosis and 15 (71.4%) patients with poor prognosis were positive for RARB methylation, which were significantly higher than controls (P<0.0001). p16 promoter methylation was shown in 19.0% and 47.6% patients with good and poor prognosis, respectively. The RARB and p16 promoter methylation in the poor prognosis group was significantly higher than that in the good prognosis group (P =0.02 for RARB and P<0.0001 for p16).
Hypermethylation of RARB and p16 promoters may predict prognosis in prostate cancer.
Prostate cancer; CpG island; DNA methylation; Retinoic acid receptor beta (RARB); CDKN2 (p16/MTS1); Methylation Specific PCR
Transrectal ultrasound–guided core biopsies of the prostate gland and prostatectomies have become common procedures at many community hospitals in Canada, especially in the era of serum prostate-specific antigen (PSA) screening for prostate cancer. The Gleason grading of prostate cancer in biopsies and prostatectomies is a major determinant used for treatment planning. There is evidence in the literature that suggests important discordance between community hospital pathologists and urological pathologists with respect to the Gleason grading of prostate cancer. Our objective was to determine the diagnostic rates and Gleason scoring patterns for prostate gland biopsies and prostatectomies at our institution compared with the literature.
We conducted a retrospective review of all prostate gland biopsies and prostatectomies performed at the Grey Bruce Health Services from January 2005 to September 2005. We collected data from 194 biopsies and 44 prostatectomies. We obtained prebiopsy serum PSA levels and digital rectal exam results for all patients from urologists’ office records.
The average age for men having biopsies was 65.8 (standard deviation [SD] 8.6) years, and the average prebiopsy serum PSA level was 8.7 (median 7.1, SD 6.2) μg/L. The rates of diagnosis from prostate gland biopsies of benign (17.6%), high-grade prostatic intraepithelial neoplasia (11.0%), atypical small acinar proliferation suspicious for invasive malignancy (13.2%) and invasive prostatic adenocarcinoma (58.2%) at our institution were significantly different than those reported in the literature (p < 0.001). We observed a significant variation in the rates of these diagnoses among the community hospital pathologists in our study (p = 0.004). There was a strong correlation between the increasing number of positive core biopsy sites and increasing Gleason scores in biopsies (p < 0.001). There was also a strong correlation between increasing pre-biopsy serum PSA levels and increasing Gleason scores in biopsies (p < 0.001). A substantial proportion (21.9%) of the biopsies given the Gleason score of 6 had a Gleason score of 7 in the prostatectomy specimen.
Our results showed a significant difference in prostate gland biopsy categorical diagnoses compared with the literature. There were also significant differences in categorical diagnoses of prostate gland biopsies among the community hospital pathologists in our study. The data identify a strong positive correlation between the increasing number of positive core biopsy sites and increasing Gleason scores in biopsies, as well as a strong positive correlation between increasing prebiopsy serum PSA levels and increasing Gleason scores in biopsies that revealed cancer. We would encourage other community hospital pathologists, in collaboration with their urologists, to review periodically their prostate gland pathology practices in an attempt to improve the uniformity of diagnoses.
To assess the accuracy of Gleason grading/scoring on preoperative needle core biopsy (NCB) compared to the radical prostatectomy (RP) specimen.
Materials and Methods:
Data of NCB and RP specimens was analyzed in 193 cases. Gleason grade/scoring was done on both NCB and RP specimens. Sixteen cases were excluded for various reasons. The Gleason scores of the two sets of matched specimens were compared and also correlated with the PSA, age, and number of needle biopsy cores. The overall change was also correlated with the initial score on NCB.
The mean age and PSA were 63.3±2(5.27) years and 18.48±2(28.42) ng/ml, respectively. The average Gleason score increased from 5.51 ± 2(1.52) to 6.2 ± 2(1.42) (P<0.02). The primary grade increased in 57 (32.2%) cases. Overall, 97 (54.8%) cases had an increase in Gleason score. Five other cases had a change from 3 + 4 = 7 to 4 + 3 = 7. Change in Gleason score was significantly more if the score on NCB was ≤6 or number of needle cores was ≤6. Besides, 28 cases had perineural invasion, 16 had capsular invasion (pT3a), and 4 had vascular invasion on RP specimen.
There is a significant upgrading of Gleason score on RP specimens when compared with NCB. This trend may be correlated positively with lower initial Gleason score on preoperative biopsy and the lower number of cores taken.
Cancer prostate; gleason grade; gleason score; needle core biopsy; radical prostatectomy
Apoptosis is a form of programmed cell death necessary for the regulation of the size of organs in adult life. Disruption of apoptotic pathways has been suggested as an important regulatory mechanism in prostatic tumours. The aim of this study was to examine the expression of apoptosis-regulating genes bcl-2 and p53 using immunohistochemistry, and the Gleason score in core needle biopsy specimens of prostate adenocarcinoma. We studied bcl-2 and p53 expression in 30 cases of low-, 30 cases of intermediate- and 20 cases of high-grade prostate adenocarcinoma. Overexpression of bcl-2 and p53 were noted in 54 and 61 of 80 patients (67.5 and 76.25%), respectively. The statistical analysis of the present data suggested that there is significant relation between p53 and bcl-2 expression, and Gleason score in prostate cancer. Thus, immunohistochemistry is a useful investigative parameter in assessing apoptosis to analyse the prognosis of prostatic tumours.
prostate; adenocarcinoma; apoptosis; immunohistochemistry
Approximately 40% of males with low Gleason grade clinically localized prostate cancer (PCa) at biopsy were finally diagnosed with high Gleason grade PCa at radical prostatectomy (RP). Therefore, a more reliable assessment of the Gleason grade prior to RP is required. Readily available modalities such as circulating biomarkers may be useful for this purpose. The aim of this study was to evaluate the ability of preoperative interleukin 6 (IL‑6) and its soluble receptor (sIL‑6R), as well as urokinase-type plasminogen activator (u-PA), its receptor (u-PAR) and the inhibitor (PAI-1) to predict Gleason score upgrading. A total of 51 PCa patients with biopsy Gleason score ≤7 were studied. IL‑6 and sIL‑6R, uPA, uPAR and PAI-1 preoperative serum levels were determined. Differences in the median and mean values of the preoperative blood levels of all biomarkers between patients with and without Gleason score upgrading were tested. The prognostic performance of each biomarker was further assessed by means of receiver operating characteristic (ROC) curves. The results showed the sIL‑6R and sIL‑6R/IL-6 ratio median levels to be significantly higher in patients who had Gleason score upgrading from ≤7 at biopsy to >7 at RP (p=0.024 and p=0.011, respectively). The ROC curve revealed that sIL‑6R and the sIL‑6R/IL‑6 ratio identified subjects at a high risk of upgrading [area under curve (AUC)=0.80 and AUC=0.83, respectively] with similar sensitivity and higher specificity for the ratio. The findings suggest that preoperative sIL‑6R and sIL‑6R/IL‑6 ratio determination in serum are useful as prognostic biomarkers in PCa patients.
The distribution of α6/α3 integrin in adhesion complexes at the basal membrane in human normal and cancer prostate glands was analyzed in 135 biopsies from 61 patients. The levels of the polarized α6/α3 integrin expression at the basal membrane of prostate tumor glands were determined by quantitative immunohistochemistry. The α6/α3 integrin expression was compared with Gleason sum score, pathological stage, and preoperative serum prostate -specific antigen (PSA). The associations were assessed by statistical methods. Eighty percent of the tumors expressed the α6 or α3 integrin and 20% was integrin-negative. Gleason sum score, but not serum PSA, was associated with the integrin expression. Low Gleason sum score correlated with increased integrin expression, high Gleason sum score with low and negative integrin expression. Three prostate tumor phenotypes were distinguished based on differential integrin expression. Type I coexpressed both α6 and α3 subunits, type II exclusively expressed α6 integrin, and type III expressed α3 integrin only. Fifteen cases were further examined for the codistribution of vinculin, paxillin, and CD 151 on frozen serial sections using confocal laser scanning microscopy. The α6/α3 integrins, CD151, paxillin, and vinculin were present within normal glands. In prostate carcinoma, α6 integrin was colocalized with CD 151, but not with vinculin or paxillin. In tumor phenotype I, the α6 subunit did not colocalize with the α3 subunit indicating the existence of two different adhesion complexes. Human prostate tumors display on their cell surface the α6β1 and/or α3β1 integrins. Three tumor phenotypes associated with two different adhesion complexes were identified, suggesting a reorganization of cell adhesion structures in prostate cancer.
prostate cancer; focal adhesion proteins; α6/α3 integrin; CD 151