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Thread: (D) Pathology – PC Science – Gleason Scoring

  1. #11
    [#6] Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized Prostate Cancer Impacts Molecular Classifications and Genomic Prognosticators [2017, Full Text]



    Next-generation sequencing is revealing genomic heterogeneity in localized prostate cancer (CaP). Incomplete sampling of CaP multiclonality has limited the implications for molecular subtyping, stratification, and systemic treatment.

    To determine the impact of genomic and transcriptomic diversity within and among intraprostatic CaP foci on CaP molecular taxonomy, predictors of progression, and actionable therapeutic targets.

    Design, setting, and participants
    Four consecutive patients with clinically localized National Comprehensive Cancer Network intermediate- or high-risk CaP who did not receive neoadjuvant therapy underwent radical prostatectomy at Roswell Park Cancer Institute in June–July 2014. Presurgical information on CaP content and a customized tissue procurement procedure were used to isolate nonmicroscopic and noncontiguous CaP foci in radical prostatectomy specimens. Three cores were obtained from the index lesion and one core from smaller lesions. RNA and DNA were extracted simultaneously from 26 cores with ≥90% CaP content and analyzed using whole-exome sequencing, single-nucleotide polymorphism arrays, and RNA sequencing.

    Outcome measurements and statistical analysis
    Somatic mutations, copy number alternations, gene expression, gene fusions, and phylogeny were defined. The impact of genomic alterations on CaP molecular classification, gene sets measured in Oncotype DX, Prolaris, and Decipher assays, and androgen receptor activity among CaP cores was determined.

    Results and limitations
    There was considerable variability in genomic alterations among CaP cores, and between RNA- and DNA-based platforms. Heterogeneity was found in molecular grouping of individual CaP foci and the activity of gene sets underlying the assays for risk stratification and androgen receptor activity, and was validated in independent genomic data sets. Determination of the implications for clinical decision-making requires follow-up studies.

    Genomic make-up varies widely among CaP foci, so care should be taken when making treatment decisions based on a single biopsy or index lesions.

    Patient summary
    We examined the molecular composition of individual cancers in a patient's prostate. We found a lot of genetic diversity among these cancers, and concluded that information from a single cancer biopsy is not sufficient to guide treatment decisions.
    [Emphasis mine]

  2. #12
    Impact of tertiary Gleason pattern 5 on prostate cancer aggressiveness: Lessons from a contemporary single institution radical prostatectomy series
    [2015, Full Text]



    To better evaluate tertiary Gleason pattern reporting and to evaluate the impact of tertiary Gleason pattern 5 (TP5) on prostate cancer pathological features and biochemical recurrence at our large single institution.

    We retrospectively reviewed 1962 patients who underwent radical prostatectomy (RP) for prostate cancer; TP5 was reported in 159 cases (8.1%). Men with Gleason score (GS) 7 and GS 8 disease were divided into subgroups with and without TP5, and histopathological features were compared. Multivariate analyses were conducted to assess the impact on TP5 on biochemical-free survival (BFS).

    Tumors possessing GS 3 + 4 with TP5 were more likely to exhibit extraprostatic extension (EPE) and had a larger tumor diameter (TD) than GS 3 + 4 alone. GS 3 + 4 with TP5 was also associated with positive surgical margins (SM), seminal vesicle involvement (SVI), and higher pre-operative prostate-specific antigen (PSA) values, but without statistical significance. GS 4 + 3 with TP5 more commonly presented with EPE, positive SM, SVI, and greater TD and pre-operative PSA level than GS 4 + 3 alone. In multivariate analysis, Gleason score, EPE, and TP5 were overall independent risk factors for PSA recurrence in this cohort. Additionally, GS 4 + 3 with TP5 was associated with shorter time to recurrence versus GS 4 + 3 alone.

    Our results emphasize the importance of TP5 and suggest that criteria for tertiary pattern reporting in prostate cancer should be standardized. Further studies are needed to evaluate the role of tertiary patterns in prognostic models.

  3. #13
    [#8] Low-Risk Prostate Cancer and Tumor Upgrading in the Surgical Specimen: Analysis of Clinical Factors Predicting Tumor Upgrading in a Contemporary Series of Patients Who were Evaluated According to the Modified Gleason Score Grading System [2017, Full Text]



    To identify significant clinical factors associated with prostate cancer (PCa) upgrading the low-risk PCa patients graded according to the modified Gleason score system.

    Materials and Methods
    The logistic regression model was used to evaluate the records of 438 patients.

    There were 170 cases (38.8%) of low-risk PCa and tumors were upgraded in 111 patients (65.3%). Only prostate specific antigen (PSA) and the proportion of positive cores (P+) were independent predictors of tumor upgrading. Further exploration was investigated by categorizing and regressing PSA (≤ 5.0 vs. > 5.0 ng/ml) and P+ (≤ 0.20 vs. > 0.20). The odds ratio of PSA > 5 ng/ml was 1.32 and of P+ > 0.20 was 2.71. The population was stratified into very low-risk with PSA ≤ 5 ng/ml and P+ ≤ 0.20 (class A), low-risk with PSA > 5 ng/ml and P+ ≤ 0.20 (class B), intermediate risk with PSA ≤ 5 ng/ml and P+ > 0.20 (class C), and high risk with PSA > 5 ng/ml and P+ 0.20 (class D). Upgrading rates were extremely low in class A (9%), extremely high in D (50.5%), and moderate (20%) in B and C.

    Patients diagnosed with low-risk PCa at biopsy are a heterogeneous population because they include subsets with undetected high-grade disease. Significant clinical predictors of upgrading include the PSA value and P+. In low-risk PCa, we identified a high-risk upgrading subgroup that needed repeat biopsies in order to reclassify the tumor grade and to reassess the clinical risk category.
    [Emphasis mine]

  4. #14
    [#9] Clinical Significance of Prospectively Assigned Gleason Tertiary Pattern 4 in Contemporary Gleason Score 3+3 =6 Prostate Cancer [2016, Full Text]



    To determine the oncologic impact of prospectively assigned tertiary pattern 4 in contemporary Gleason score (GS) 3 +3 =6 radical prostatectomy (RP) specimens.

    Oncologic outcomes were retrospectively reviewed for 720 consecutive patients from a single National Comprehensive Cancer Network (NCCN) center with at least 6 months follow-up after RP for GS3 +3 =6 (GS6, N =222), GS6 with tertiary pattern 4 (GS6t4, N =62), or GS3 +4 =7 (N =436) prostate cancer, as prospectively graded since 2006 using the 2005 International Society of Urologic Pathologists criteria. Preoperative NCCN risk category, RP pathology, progression-free survival (PFS) and metastasis-free survival (MFS) were compared among the GS6, GS6t4, and GS3 +4 =7 groups using χ2, Kaplan–Meier, and log-rank analyses.

    The incidence of low NCCN preoperative risk classification for GS6t4 patients (63%) was less than that for GS6 patients (77%) while greater than that for GS3 +4 =7 patients (30%, P <0.001). GS6t4 patients had RP pathologic features which were intermediate in risk between that of GS6 and GS3 +4 =7 based on extraprostatic extension (27% vs. 6% vs. 31%, respectively, P <0.001) and mean percentage of prostate gland involvement (13% vs. 10% vs. 16%, respectively, P <0.001). With a mean overall follow-up of 42 months, PFS for GS6t4 patients (5-year 85%) was intermediate between that of GS6 (5-year 93%) and GS3 +4 =7 (5-year 76%) patients (P <0.001). The 5-year MFS rate was 100% for GS6 and GS6t4 patients compared to 97% for GS3 +4 =7 patients (P =0.07).

    This study provides the longest follow-up to date for RP patients with prospectively assigned GS6t4 and supports a risk for adverse RP pathology and postoperative disease progression that is intermediate between GS6 and GS3 +4 =7. Whether a tertiary pattern 4 in GS6 disease increases the risk of metastasis is uncertain and requires longer term study. Given favorable oncologic outcomes, less stringent postoperative surveillance for both GS6 and GS6t4 patients may be warranted.
    [Emphasis mine]

  5. #15
    [#10] Frequency of Gleason score 7 to 10 in 5100 elderly prostate cancer patients [2016, Full Text]



    Men 70 to 80 years of age are known to have an increased incidence of high-grade (Gleason sum score [GSS] 7–10) prostate cancer. We determined the frequency of highgrade prostate cancer among men 70 to 80 years old in our practice. We retrospectively reviewed our 5100 prostate cancer patients who are 70 to 80 years old and who opted for radiation therapy (external radiation, brachytherapy, or combination). Data were gathered on race, prostate-specific antigen value, digital rectal examination (DRE) results, and GSS. Patients were further subdivided by age in two categories, those 70 to 75 years and 76 to 80 years, and also by time period: 2006–2010 and 2011–2015. In patients 70 to 75 years, 1426 patients had a GSS of 6 (41%) and 2042 patients had a GSS of 7 to 10 (59%). In patients 76 to 80 years old, 553 had a GSS of 6 (34%) and 1079 had a GSS of 7 to 10 (66%). In 1432 patients with an abnormal DRE result, the GSS was 6 in 376 (26%) and GSS was 7 to 10 in 1059 (74%). Based on analysis of 5100 prostate cancer patients in our practice, we determined that 61% of patients age 70 to 80 have a high-grade prostate cancer, as do 59% of patients age 70 to 75 years, and 66% of patients between age 76 and 80 years. Because biopsy underestimates the grade in GSS 6 patients by 50%, the actual frequency is approximately 80%. In patients with prostate cancer who had an abnormal DRE result, 74% had a GSS of 7 to 10—approximately 85% when accounting for biopsy under-grading.

  6. #16
    Resolving the Coffey Paradox: what does the androgen receptor do in normal vs. malignant prostate epithelial cells?
    [2018, Full Text]



    Donald Straley Coffey completed his 85 year life’s journey on November 9, 2017. In his wake, he left a legion of inspired and loyal students, fellows, and faculty colleagues from all over the world to carry on his passion both for life in general and his 50 year quest to conquer cancer. Early in his career, Dr. Coffey developed a series of animal models to study how androgen regulates the growth of both normal and abnormal prostatic epithelium. As part of these early studies, Dr. Coffey uncovered a paradox in that anti-androgen treatment given at the “wrong” time paradoxically enhanced, not inhibited, normal prostate growth. Advances over the last several years concerning the paracrine-dependent stem cell organization of the prostate provide a mechanistic explanation for this “Coffey Paradox”. This is based upon the realization that the normal function of the Androgen Receptor (AR) in the paracrine-dependent stem cell organization of the prostate is to induce terminal differentiation of normal prostate epithelial cells while suppressing their growth, despite the presence of high levels of stromal cell-derived paracrine growth factors. Such growth suppression involves ligand-dependent AR binding to the Tcf-4/β-catenin 3’c-Myc enhancer in prostate epithelial cells, which inhibits c-Myc transcription needed for proliferation. Therefore, if anti-androgen is given at the wrong time, it prevents such AR-dependent c-Myc down regulation, and thus paradoxically enhances epithelial regrowth (i.e. the Coffey Paradox) induced by exogenous androgen replacement in the castration regressed prostate. In contrast to the normal prostate epithelium, in prostate cancer cells retaining AR expression, androgen-induced AR signaling no longer reduces c-Myc transcription but instead up-regulates c-Myc translation and protein stability to stimulate malignant growth. Thus, in these AR expressing prostate cancer cells, AR signaling is converted from a growth suppressor to an oncogene, which involves a gain of function to upregulate c-Myc protein expression. Such a gain of function “addicts” these prostate cancer cells to AR signaling for their proliferation and survival, which provides the rationale for therapy targeted at inhibiting such AR signaling. While therapies targeted at maximally decreasing the level of androgen ligand are the most commonly used, recent studies have documented that a subset of patients progressing on such androgen ablation (i.e. castration-resistant disease) due to their adaptive increase in AR protein expression respond positively to rapid cycling between pharmacologically high and castration low levels of circulating androgen. [i.e. Bipolar Androgen Therapy (BAT)].
    Last edited by DjinTonic; 04-28-2018 at 10:11 AM.

  7. #17
    Metastases in Prostate Cancer



    Prostate cancer (PCa) prognosis and clinical outcome is directly dependent on metastatic occurrence. The bone microenvironment is a favorable metastatic niche. Different biological processes have been suggested to contribute to the osteotropism of PCa such as hemodynamics, bone-specific signaling interactions, and the “seed and soil” hypothesis. However, prevalence of disseminating tumor cells in the bone is not proportional to the actual occurrence of metastases, as not all patients will develop bone metastases. The fate and tumor-reforming ability of a metastatic cell is greatly influenced by the microenvironment. In this review, the molecular mechanisms of bone and soft-tissue metastasis in PCa are discussed. Specific attention is dedicated to the residual disease, novel approaches, and animal models used in oncological translational research are illustrated.
    Last edited by DjinTonic; 04-28-2018 at 10:11 AM.

  8. #18
    The inflammatory microenvironment and microbiome in prostate cancer development



    Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.
    [Emphasis mine]
    Last edited by DjinTonic; 04-28-2018 at 10:12 AM.

  9. #19

    https://www.jurology.com/article/S0022-5347(18 )40985-8/abstract
    Emoticon interference: remove the space after the 8

    CONCLUSIONS All patients with prostate needle biopsy GS8 are assigned to high-risk groups, though low GS8 tumor volume and the presence of pattern 3 in other cores suggests pathological and staging outcomes more consistent with intermediate risk disease....
    Last edited by DjinTonic; 04-28-2018 at 10:12 AM.

  10. #20
    Intraductal Carcinoma of the Prostate: A Risk for Rapid Recurrence



    Intraductal carcinoma of the prostate (IDC-P), recently defined by the World Health Organization in 2016, is a distinct histologic entity associated with an aggressive clinical course, including increased risk of biochemical recurrence, metastasis, and mortality. Differential diagnosis includes intraductal spread of urothelial carcinoma, prostatic ductal carcinoma, and high-grade prostatic intraepithelial neoplasia. BRCA mutations are associated with an increased risk of IDC-P. The presence of IDC-P on initial biopsy or radical prostatectomy should trigger aggressive treatment and should be considered a contraindication to active surveillance, regardless of tumor volume.

    Population-based study of the incidence and survival for intraductal carcinoma of the prostate [2017]


    • IDC-P is associated with a 3-fold higher risk for PCSM.
    • IDC-P is associated with a greater likelihood of aggressive CaP features.
    • IDC-P is associated with a more than 2-fold higher likelihood of pT3/4 disease.


    The degree to which intraductal carcinoma of the prostate (IDC-P) affects clinical course remains poorly understood owing to small sample sizes from single-center studies. We sought to determine prognostic factors and outcomes associated with IDC-P in radical prostatectomy (RP) specimens.

    Materials and methods
    This is a retrospective study of RP during 2004 to 2013 using Surveillance, Epidemiology, and End Results to compare IDC-P with non-IDC-P. The effect of IDC-P on overall and disease-specific survival was assessed using Cox regression with a median follow-up of 4.8 years (interquartile range [IQR]: 2.6–7.0 y; P = 0.01). Median prostate-specific antigen at diagnosis in IDC-P vs. non-IDC-P was similar (P = 0.23) at 6.2 (IQR: 4.6–13.0) vs. 6.1 ng/ml (IQR: 4.6–9.8 ).

    We identified 159,777 RP from 2004 to 2013, and 242 (0.002%) had IDC-P pathologic features. IDC-P was associated with a greater likelihood of extraprostatic stage, pT3/T4, 45.9% vs. 21.6% (P<0.001), higher grade, GS≥ 7, 79.3% vs. 62.7% (P<0.001), lymph node metastases, 5.8% vs. 2.4% (P<0.001), and positive surgical margins, 25.6% vs. 19.5% (P = 0.02). IDC-P was associated with a 3-fold increase in prostate cancer-specific mortality relative to non-IDC-P (hazard ratio = 3.0, 95% CI: 1.5–5.7; P<0.01). Limitations include retrospective design and potential underreporting of IDC-P that leads to underestimation of the true effect size.

    The significance of IDC-P features has been recently recognized by the World Health Organization and it is associated with high-grade, extraprostatic features, and worse prostate cancer-specific mortality. Understanding its prognostic significance better guides adjuvant therapies and clinical trials.

    Intraductal Carcinoma of the Prostate on Diagnostic Needle Biopsy Predicts Prostate Cancer Mortality: A Population‐Based Study [2017]



    Intraductal carcinoma of the prostate (IDC‐P) is a distinct histopathologic feature associated with high‐grade, advanced prostate cancer. Although studies have shown that IDC‐P is a predictor of progression following surgical or radiation treatment for prostate cancer, there are sparse data regarding IDC‐P on diagnostic needle biopsy as a prognosticator of prostate cancer mortality.

    This was a population‐based study of all prostate cancer patients diagnosed using needle biopsy and without evidence of systemic disease between 1991 and 1999 within a defined geographic region of Norway. Patients were identified by cross‐referencing the Norwegian Cancer Registry. Of 318 eligible patients, 283 had biopsy specimens available for central pathology review. Clinical data were obtained from medical charts. We examined whether IDC‐P on diagnostic needle biopsy was associated with adverse clinicopathological features and prostate cancer mortality.

    Patients with IDC‐P on diagnostic needle biopsy had a more advanced stage and a higher Gleason score compared to patients without IDC‐P. IDC‐P was also associated with an intensively reactive stroma. The 10‐year prostate cancer‐specific survival was 69% for patients with IDC‐P on diagnostic needle biopsy and 89% for patients without IDC‐P (Log rank P‐value < 0.005). The presence of IDC‐P on diagnostic needle biopsy remained an independent predictor of prostate cancer mortality after adjustments for clinical prognostic factors and treatment. After adjustment for the newly implemented Grade Group system of prostate cancer, IDC‐P showed a strong tendency toward statistical significance. However, IDC‐P did not remain a statistically significant predictor in the multivariable analysis.

    IDC‐P on diagnostic needle biopsy is an indicator of prostate cancer with a high risk of mortality. Accordingly, a diagnosis of IDC‐P on needle biopsy should be reported and considered a feature of high‐risk prostate cancer. Moreover, the association between IDC‐P and reactive stroma provides evidence in support of the idea that stromal factors facilitate carcinoma invasion to the prostatic acini and ducts.
    Last edited by DjinTonic; 04-28-2018 at 01:22 PM.


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