OncoTherad® (MRB-CFI-1) Nanoimmunotherapy: A Promising Strategy to Treat Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer: Crosstalk among T-Cell CX3CR1, Immune Checkpoints, and the Toll-Like Receptor 4 Signaling Pathway.

This study assessed the safety and efficacy of OncoTherad® (MRB-CFI-1) nanoimmunotherapy for non-muscle invasive bladder cancer (NMIBC) patients unresponsive to Bacillus Calmette-Guérin (BCG) and explored its mechanisms of action in a bladder cancer microenvironment. A single-arm phase I/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients' mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1-2 events. OncoTherad® activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1+ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad® has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes.

Fumarate hydratase-deficient renal cell carcinoma: A tumor with diverse morphology including cannibalism, lymphocytic emperipolesis, and defective autophagy.

We report the clinicopathological findings of the first series of 3 patients from Brazil with fumarate hydratase-deficient renal cell carcinoma. The clinicopathological findings disclosed a very aggressive tumor. All 3 patients had solitary tumor at the left side, metastasis and advanced stage at the time of diagnosis; were females with a median age of 40 years; had a history of uterine leiomyomas; and, at follow-up two patients are deceased and one patient alive. The microscopic findings of these 3 patients are in accordance with the literature disclosing a variety of morphologic features being papillary arrangement, eosinophilic cytoplasm, and prominent nucleoli surrounded by clear halo the constant and most frequent findings. Previously not reported in this tumor, we describe presence of cannibalism, lymphocytic emperipolesis, and cytoplasmic vacuoles with eosinophilic inclusions associated with overexpression of p62 in immunohistochemistry which is considered to be evidence of defective autophagy. Lymphocytic emperipolesis was a more frequent finding than cannibalism and immunohistochemistry for p62 was overexpressed only in the 2 patients disclosing cytoplasmic vacuoles with eosinophilic inclusions. The presence, frequency and significance of these novel findings should be checked in large series of this rare and aggressive tumor aiming to associate with clinical behavior and eventually influence the strategy of treatment.

A novel histologic finding in male patients with bladder outlet obstruction: a possible etiopathogenesis of Marion's disease?

PURPOSE: George Marion first described primary bladder neck obstruction in 1933. Even today, the etiopathogenesis of this condition is unknown. The objective of this study is to associate a novel histologic finding with Marion's disease to contribute to its etiopathogenesis, and to seek the reason why the lower urinary tract symptoms of some patients was not relieved after pharmacological treatment. METHODS: The retrospective study was carried out with patients who underwent transurethral resection of the prostate from 2009 to 2019. Patients with histological diagnosis did not present hyperplastic nodules, and the presence of skeletal muscle fibers were included in the study. The frequency of cases with presence of skeletal muscle fibers was assessed as well as the area occupied by these fibers in each resected fragment. As a control group, fragments of bladder neck of surgical specimens from 50 radical prostatectomies were analyzed. RESULTS: In 14 patients with skeletal muscle fibers in the resected fragments the extent of each positive fragment was < 25%, > 25-50%, > 50-75%, and > 75% in 28.6%, 28.6%, 21.4%, and 21.4% fragments, respectively. In the control group, 20% (10/50) of the patients had skeletal muscle fibers and, in all cases, they occupied < 25%. CONCLUSION: In these 14 cases, the presence of skeletal muscle fibers is frequent and predominant in TURP fragments, which stands in striking contrast to the control group. We consider that presence of skeletal muscle fibers may be related to Marion's disease, thus contributing to explain its etiopathogenesis and the unsuccessful alpha-blocker treatment in these patients.

Prognostic significance of architectural subtypes of Gleason grade 4 prostate cancer in radical prostatectomy: A semiquantitative method of evaluation.

Studies have shown that Gleason grade 4 extent as well as architectural subtypes provide prognostic information. We aimed to evaluate the influence on biochemical recurrence following radical prostatectomy of patients with organ-confined tumor, Gleason score 7, and negative surgical margins. Total tumor extent, Gleason grade 4 total extent and the extent of each architectural subtype (fused glands, poorly defined glands, cribriform glands, and glomeruloid glands) were evaluated by a semiquantitative point-count method using different colors to identify each subtype. Microscopic morphology of glomeruloid glands was considered regardless of morphology: size (small or large), attachment (narrow or extensive), and cribriform or solid intraluminal protrusion. Gleason grade 4 total extent significantly predicted shorter time to biochemical recurrence in univariate and multivariate analysis. Stratifying extent, Gleason grade 4 with >30% of the total grade 4 extent was significantly predictive for time of recurrence. Considering architectural subtypes, cribriform and glomeruloid glands but not fused and poorly formed glands extent, significantly predicted shorter time to recurrence in univariate analysis. An important issue related to the studies on prognostic significance of Gleason grade 4 subtypes is the lack of uniformity in the definition of microscopic morphology of the subtypes particularly of the glomeruloid architecture.

Data set for the reporting of carcinoma of renal tubular origin: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: The International Collaboration on Cancer Reporting (ICCR) has provided detailed data sets based upon the published reporting protocols of the Royal College of Pathologists, the Royal College of Pathologists of Australasia and the College of American Pathologists. METHODS AND RESULTS: The data set for carcinomas of renal tubular origin treated by nephrectomy was developed to provide a minimum structured reporting template suitable for international use, and incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the fourth edition of the World Health Organisation Bluebook on tumours of the urinary and male genital systems published in 2016. Reporting elements were divided into those, which are required and recommended components of the report. Required elements are: specimen laterality, operative procedure, attached structures, tumour focality, tumour dimension, tumour type, WHO/ISUP grade, sarcomatoid/rhabdoid morphology, tumour necrosis, extent of invasion, lymph node status, surgical margin status, AJCC TNM staging and co-existing pathology. Recommended reporting elements are: pre-operative treatment, details of tissue removed for experimental purposes prior to submission, site of tumour(s) block identification key, extent of sarcomatoid and/or rhabdoid component, extent of necrosis, presence of tumour in renal vein wall, lymphovascular invasion and lymph node status (size of largest focus and extranodal extension). CONCLUSIONS: It is anticipated that the implementation of this data set in routine clinical practice will inform patient treatment as well as provide standardised information relating to outcome prediction. The harmonisation of data reporting should also facilitate international research collaborations.

The importance of histopathologic review of biopsies in patients with prostate cancer referred to a tertiary uro-oncology center.

INTRODUCTION: In view of the detailed histologic evaluation of prostate cancer (PC), it is usually advisable to provide a "second opinion" to confirm diagnosis. This study aimed to compare the Gleason score (GS) of initial diagnosis versus that of histopathologic review of patients with PC. The secondary objective was to compare initial GS versus histopathologic review versus post - surgical histopathology. MATERIAL AND METHODS: Retrospective study based on chart review of patients with PC that attended the Uro - oncology Department of Hospital das Clínicas - UNICAMP - Campinas, Brazil, from April, 2002, to April, 2012. Data were divided in groups: patients with biopsies performed elsewhere, biopsies after pathological review and histopathological results following retropubic radical prostatectomy (RRP). These were evaluated in relation to GS difference using Fleis's Kappa concordance coefficient. RESULTS: 402 PC patients, with a median age of 66 years, were evaluated. Reviewed GS showed worsening, with accuracy of 61.2%, and Kappa concordance value = 0.466. Among 143 patients submitted to surgery, GS varied widely, regarding initial evaluation, review and post - surgical RRP. Joint concordance of evaluations was weak (Kappa = 0.216), mainly due to almost no existence concordance between initial evaluation and following RRP (Kappa = 0.041). CONCLUSION: There is a great histopathological variation of initial GS versus reviewed GS. There is also a better correlation of reviewed GS and post - surgical GS than with initial GS. The second opinion by an uropathologist improves diagnosis and should be advised for better therapeutic decision.

The TNM 8th edition: Validation of the proposal for organ - confined (pT2) prostate cancer.

PURPOSE: The 8th edition of the TNM has been updated and improved in order to ensure a high degree of clinical relevance. A major change in prostate includes pathologically organ - confined disease to be considered pT2 and no longer subclassified by extent of involvement or laterality. The aim of this study was to validate this major change. MATERIALS AND METHODS: Prostates were step - sectioned from 196 patients submitted to radical prostatectomy with organ confined disease (pT2) and negative surgical margins. Tumor extent was evaluated by a semiquantitative point count method. The dominant nodule extent was recorded as the maximal number of positive points of the largest single focus of cancer from the quadrants. Laterality was considered as either total tumor extent (Group 1) or index tumor extent (Group 2). Time to biochemical recurrence was analyzed with the Kaplan - Meier product limit analysis and prediction of shorter time to biochemical recurrence with Cox proportional hazards model. RESULTS: In Group 1, 43 / 196 (21.9%) tumors were unilateral and 153 / 196 (78.1%) bilateral and in Group 2, 156 / 196 (79.6%) tumors were unilateral and 40 / 196 (20.4%) bilateral. In both groups, comparing unilateral vs bilateral tumors, there was no significant clinicopathological difference, and no significant association with time as well as prediction of shorter time to biochemical recurrence following surgery. CONCLUSIONS: Pathologic sub - staging of organ confined disease does not convey prognostic information either considering laterality as total tumor extent or index tumor extent. Furthermore, no correlation exists between digital rectal examination and pathologic stage.

Are 10-, 10-12-, or > 12-mm prostate biopsy core quality control cutoffs reasonable?

PURPOSE: To explore the role of prostate biopsy core length on prediction of index tumor clinical significance and localization on radical prostatectomy (RP) and time to recurrence, hypothesizing 10-, 10-12-, or > 12-mm minimum core as potential biopsy quality control. METHODS: Assessed 2424 prostate biopsy cores and corresponding RP of 202 patients submitted to the first set of 12 cores prostate biopsy between 2010 and 2015. Analyzed biopsy core length, age, prostate volume (PV), free and total PSA ratio, PSA density, RP index tumor clinical significance, extension, localization, surgical margins, and cancer control. Prostate biopsy confronted to surgical specimens defined Gleason grade-grouping system (1-5) agreement. RESULTS: Median age was 63.7 years, PSA 10.1 ng/dl, PSA density 28%, and mean follow-up 5 years. Recurrence was identified in 64 (31.7%) patients and predicted by PSA > 10 at time of diagnosis (p = 0.008), seminal vesicle invasion (p = 0.0019), core tumor percentage (p = 0.033), and tumor localization predominantly in the prostate base (p = 0017). The mean core length was longer in index tumor positive cores (p = 0.043) and in tumors classified as clinically insignificant (p = 0.011), without impact on tumor localization (basal vs apical p = 0.592; left vs. right p = 0.320). Biopsy core length categories (≤ 10, 10-12 and > 12 mm) did not significantly impact Gleason grade-grouping agreement or time to recurrence (p > 0.05). Core length was not significantly different in all Gleason grade-groupings 1-5 (p = 0.312). CONCLUSION: Prostate biopsy core length impacts tumor characterization; however, 10 mm minimum core length and even 10-12- and > 12-mm categories failed as a biopsy quality control in our data.

Does index tumor predominant location influence prognostic factors in radical prostatectomies?

PURPOSE: To find any influence on prognostic factors of index tumor according to predominant location. MATERIALS AND METHODS: Prostate surgical specimens from 499 patients submitted to radical retropubic prostatectomy were step-sectioned. Each transverse section was subdivided into 2 anterolateral and 2 posterolateral quadrants. Tumor extent was evaluated by a semi-quantitative point-count method. The index tumor (dominant nodule) was recorded as the maximal number of positive points of the most extensive tumor area from the quadrants and the predominant location was considered anterior (anterolateral quadrants), posterior (posterolateral quadrants), basal (quadrants in upper half of the prostate), apical (quadrants in lower half of the prostate), left (left quadrants) or right (right quadrants). Time to biochemical recurrence was analyzed by Kaplan-Meier product-limit analysis and prediction of shorter time to biochemical recurrence using univariate and multivariate Cox proportional hazards model. RESULTS: Index tumors with predominant posterior location were significantly associated with higher total tumor extent, needle and radical prostatectomy Gleason score, positive lymph nodes and preoperative prostate-specific antigen. Index tumors with predominant basal location were significantly associated with higher preoperative prostate-specific antigen, pathological stage higher than pT2, extra-prostatic extension, and seminal vesicle invasion. Index tumors with predominant basal location were significantly associated with time to biochemical recurrence in Kaplan-Meier estimates and significantly predicted shorter time to biochemical recurrence on univariate analysis but not on multivariate analysis. CONCLUSIONS: The study suggests that index tumor predominant location is associated with prognosis in radical prostatectomies, however, in multivariate analysis do not offer advantage over other well-established prognostic factors.

Gleason grade 4 prostate adenocarcinoma patterns: an interobserver agreement study among genitourinary pathologists.

AIMS: To assess the interobserver reproducibility of individual Gleason grade 4 growth patterns. METHODS AND RESULTS: Twenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. 'Consensus' was defined as at least 80% agreement, and 'favoured' as 60-80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern ('complex fused'). CONCLUSIONS: Consensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached.

Intravesical bacillus Calmette-Guérin efficiently reduces p70S6K1 but not 4E-BP1 phosphorylation in nonmuscle invasive bladder cancer.

PURPOSE: We characterized the functional consequences of intravesical bacillus Calmette-Guérin on the molecular mechanism of the AKT/mTOR signaling pathway in nonmuscle invasive bladder cancer. To our knowledge this has not been reported previously. MATERIALS AND METHODS: At age 7 weeks female Fischer 344 rats received 1.5 mg/kg MNU intravesically every other week for 6 weeks. They were randomized at 10 per group to MNU (0.2 ml vehicle), bacillus Calmette-Guérin (10(6) cfu Connaught strain), rapamycin (15 µg/ml) and bacillus Calmette-Guérin plus simultaneous rapamycin, each intravesically for 6 weeks. At week 15 the bladders were collected for histopathology, immunohistochemistry and immunoblot to determine p-AKT, Rictor, Raptor, p-4E-BP1, p-p70S6K1, p-AMPK-α, p-mTOR and p-p53. RESULTS: Papillary carcinoma (pTa) and high grade intraepithelial neoplasia (pTis) predominated in the MNU group while normal urothelium, papillary and flat hyperplasia were more common in treated groups. Nonmuscle invasive bladder cancer treated with bacillus Calmette-Guérin showed suppression of p70S6K1 but not 4E-BP1 phosphorylation. This suggests that 4E-BP1 is regulated differently than p70S6K1, escaping the bacillus Calmette-Guérin action that occurs in a mTOR independent manner. The association of bacillus Calmette-Guérin with rapamycin but not rapamycin monotherapy affected p70S6K1 and 4E-BP1 phosphorylation with no features of in situ carcinoma (pTis). CONCLUSIONS: The activation status of p70S6K1 and 4E-BP1 might be used to stratify patients who could benefit from targeting such molecular elements with multitarget/multidrug intravesical therapy. In the future 4E-BP1 might be a worthwhile new target for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.

Urothelial carcinogen resistance driven by stronger Toll-like receptor 2 (TLR2) and Uroplakin III (UP III) defense mechanisms: a new model.

OBJECTIVE: The objective of the study was to illustrate the applicability and significance of the novel Lewis urothelial cancer model compared to the classic Fisher 344. METHODS: Fischer 344 and Lewis females rats, 7 weeks old, were intravesical instilled N-methyl-N-nitrosourea 1.5 mg/kg every other week for a total of four doses. After 15 weeks, animals were sacrificed and bladders analyzed: histopathology (tumor grade and stage), immunohistochemistry (apoptotic and proliferative indices) and blotting (Toll-like receptor 2-TLR2, Uroplakin III-UP III and C-Myc). Control groups received placebo. RESULTS: There were macroscopic neoplastic lesions in 20 % of Lewis strain and 70 % of Fischer 344 strain. Lewis showed hyperplasia in 50 % of animals, normal bladders in 50 %. All Fischer 344 had lesions, 20 % papillary hyperplasia, 30 % dysplasia, 40 % neoplasia and 10 % squamous metaplasia. Proliferative and apoptotic indices were significantly lower in the Lewis strain (p < 0.01). The TLR2 and UP III protein levels were significantly higher in Lewis compared to Fischer 344 strain (70.8 and 46.5 % vs. 49.5 and 16.9 %, respectively). In contrast, C-Myc protein levels were significantly higher in Fischer 344 (22.5 %) compared to Lewis strain (13.7 %). CONCLUSIONS: The innovative Lewis carcinogen resistance urothelial model represents a new strategy for translational research. Preservation of TLR2 and UP III defense mechanisms might drive diverse urothelial phenotypes during carcinogenesis in differently susceptible individuals.

Gleason underestimation is predicted by prostate biopsy core length.

PURPOSE: To evaluate whether core length impacts biopsy accuracy and Gleason score underestimation compared to radical prostatectomy (RP) specimens. METHODS: From 2010 to 2011, 8,928 cores were trans-rectal obtained from 744 consecutive patients (178 RP, 24%), 557 by an experienced performer (>250/year) and 187 (25%) by in-training urology residents. Prospectively analyzed variables were core length, age, prostate volume, free and total prostate-specific antigen (PSA), PSA density and free/total PSA ratio. RESULTS: Mean core length for Gleason upgrading on RP (42.7%, n = 76) was 11.61 (±2.5, median 11.40) compared to 13.52 (±3.2, median 13.70), p < 0.001 for perfect biopsy-RP Gleason agreement (57.3%, n = 102). In multivariate analysis, for each unit of core length increment in millimeter, the Gleason upgrading risk decreased 89.9%, p = 0.049 [odds ratio (OR) 0.10, 95% confidence interval (CI) 0.01-0.99]. Biopsy positivity between experienced (35.5%) and in-training performer (30.1%) was not significantly different (p = 0.20), with comparable mean patient age (65.1 vs. 64.1), prostate volume (52.3 vs. 50.7) and median PSA (5.2 vs. 5.1), respectively. Denoting wider variability in terms of core length, in-training performers obtained significantly larger cores for positive biopsies (11.33 ± 3.42 vs. 10.83 ± 3.68), p = 0.043, compared to experienced performer (11.39 ± 3.36 vs. 11.37 ± 3.64), p = 0.30. In multivariate analysis, PSA density (OR 1.14, 95% CI 1.02-1.28) and age (OR 1.04, 95% CI 1.01-1.07) were significantly associated with biopsy positivity, p = 0.021 and p = 0.011, respectively. CONCLUSION: While core length on trans-rectal biopsy independently affects Gleason upgrading on RP specimens, performer experience has minor impact on Gleason discordance or biopsy positivity due to a sharp learning curve.

Predictive criteria of insignificant prostate cancer: what is the correspondence of linear extent to percentage of cancer in a single core?

OBJECTIVE: The aim of active surveillance of early prostate cancer is to individualize therapy by selecting for curative treatment only patients with significant cancer. Epstein's criteria for prediction of clinically insignificant cancer in surgical specimens are widely used. Epstein's criterion "no single core with >50% cancer has no correspondence in linear extent. The aim of this study is to find a possible correspondence. MATERIALS AND METHODS: From a total of 401 consecutive patients submitted to radical prostatectomy, 17 (4.2%) met criteria for insignificant cancer in the surgical specimen. The clinicopathologic findings in the correspondent biopsies were compared with Epstein's criteria for insignificant cancer. Cancer in a single core was evaluated in percentage as well as linear extent in mm. RESULTS: Comparing the clinicopathologic findings with Epstein's criteria predictive of insignificant cancer, there was 100% concordance for clinical stage T1c, no Gleason pattern 4 or 5, ≤ 2 cores with cancer, and no single core with >50% cancer. However, only 25% had density ≤ 0.15. The mean, median and range of the maximum length of cancer in a single core in mm were 1.19, 1, and 0.5-2.5, respectively. Additionally, the mean, median, and range of length of cancer in all cores in mm were 1.47, 1.5, and 0.5-3, respectively. CONCLUSION: To pathologists that use Epstein's criteria predictive of insignificant cancer and measure linear extent in mm, our study favors that "no single core with >50% cancer" may correspond to >2.5 mm in linear extent.

Characterization of reactive stroma in prostate cancer: involvement of growth factors, metalloproteinase matrix, sexual hormones receptors and prostatic stem cells.

INTRODUCTION AND OBJECTIVES: Reactive Stroma (RStr) is observed in many human cancers and is related to carcinogenesis. The objectives of the present study were to stablish a relationship of the RStr microenvironment with prostate cancer (Pca) through a morphological and molecular characterization, and to identify a possible relationship between RStr with worse prognosis factors and occurrence of malignant prostatic stem cells. MATERIALS AND METHODS: Forty prostatic samples were selected from men with Pca diagnosis submitted to radical prostatectomy; they were divided in two groups: Group-1 (n=20): samples without reactive stroma; Group-2 (n=20): samples of PCa with intense stroma reaction. Prostatic samples were evaluated for RStr intensity by Masson Trichromic stain and posteriorly submitted to histopathological and immunohistochemistry analysis for antigens: a-actin, vimentin, IGF-1, MMP-2, FGF-2, C-Myc, PSCA, AR, Era and ERß. RESULTS: Reactive stroma with intense desmoplastic reactivity was significantly more frequent in intermediate (Gleason 7, 3+4) and high grade tumors (Gleason 7, 4+3). The group with intense stromal reactivity showed significant higher levels of Vimentin, IGF-1, MMP-2, FGF-2, C-Myc, PSCA and ERa. CONCLUSIONS: It can be concluded that RStr may be a predictive marker of Pca progression, since it was associated with increase of growth factors, imbalance of androgen and estrogen receptors and presence of malign prostatic stem cells.

Diagnostic criteria for ductal adenocarcinoma of the prostate: interobserver variability among 20 expert uropathologists.

AIMS: Ductal adenocarcinoma of the prostate (DAC) is clinically important, because its behaviour may differ from that of acinar adenocarcinoma. Our aims were to investigate the interobserver variability of this diagnosis among experts in uropathology and to define diagnostic criteria. METHODS AND RESULTS: Photomicrographs of 21 carcinomas with ductal features were distributed among 20 genitourinary pathologists from eight countries. DAC was diagnosed by 18 observers (mean 13.2 cases, range 6-19). In 11 (52%) cases, a 2/3 consensus was reached for a diagnosis of DAC, and in five (24%) there was consensus against. In DAC, the respondents reported papillary architecture (86%), stratification of nuclei (82%), high-grade nuclear features (54%), tall columnar epithelium (53%), elongated nuclei (52%), cribriform architecture (40%), and necrosis (7%). The most important diagnostic feature reported for DAC was papillary architecture (59%), whereas nuclear and cellular features were considered to be most important in only 2-11% of cases. The most common differential diagnoses were intraductal prostate cancer (52%), high-grade PIN (37%), and acinar adenocarcinoma (17%). The most common reason for not diagnosing DAC was lack of typical architecture (33%). CONCLUSIONS: Papillary architecture was the most useful diagnostic feature of DAC, and nuclear and cellular features were considered to be less important.

Supporting prostate cancer focal therapy: a multidisciplinary International Consensus of Experts ("ICE").

Prostate cancer is a common malignancy among men, and the current screening, imaging and sampling approaches aim to detect early-stage, organ-confined disease. In such scenario, focal prostate cancer therapy currently relies on the index lesion concept as the dominant lesion that drives the disease natural history. Focal therapy demands the essential imaging and sampling techniques to strategically locate and qualify the disease, but, despite advances in technology, prostate imaging and biopsy have several limitations that need to be overcome if focal therapy is to be developed further. The I Prostate Cancer Focal Treatment International Symposium was convened to foster discussion on this topic that sits at the crossroads of multiple disciplines (Urology, Pathology, Radiology, Radiation Oncology and Medical Oncology) all of which were represented for this comprehensive multidisciplinary review of the current literature.

Intraductal carcinoma of the prostate: interobserver reproducibility survey of 39 urologic pathologists.

The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.

[Renal tumors: The International Society of Urologic Pathology (ISUP) 2012 consensus conference recommendations]. / Les tumeurs rénales : recommandations de la conférence de consensus de l'International Society of Urologic Pathology (ISUP) 2012.

During the last 30 years many advances have been made in kidney tumor pathology. In 1981, 9 entities were recognized in the WHO Classification. In the latest classification of 2004, 50 different types have been recognized. Additional tumor entities have been described since and a wide variety of prognostic parameters have been investigated with variable success; however, much attention has centered upon the importance of features relating to both stage and grade. The International Society of Urological Pathology (ISUP) recommends after consensus conferences the development of reporting guidelines, which have been adopted worldwide ISUP undertook to review all aspects of the pathology of adult renal malignancy through an international consensus conference to be held in 2012. As in the past, participation in this consensus conference was restricted to acknowledged experts in the field.

Prostate total tumor extent versus index tumor extent--which is predictive of biochemical recurrence following radical prostatectomy?

PURPOSE: It is controversial whether tumor extent in radical prostatectomies predicts biochemical recurrence following surgery. We compared the predictive value of total tumor extent vs dominant nodule (index tumor) extent. MATERIALS AND METHODS: A mean of 32 paraffin blocks was processed from prostate surgical specimens step sectioned at 3 to 5 mm intervals from 300 patients treated with radical retropubic prostatectomy. Each transverse section was subdivided into 2 anterolateral and 2 posterolateral quadrants. Tumor extent was evaluated by a semiquantitative point count method. Dominant nodule extent was recorded as the maximal number of positive points of the largest single focus of cancer in the quadrants. Time to biochemical recurrence was analyzed by Kaplan-Meier product limit analysis. Prediction of shorter time to biochemical recurrence was determined by univariate and multivariate Cox proportional hazards models. RESULTS: Except for age and race, total and index tumor extent was significantly associated with higher preoperative prostate specific antigen, clinical stage T2, pathological stage greater than T2, positive surgical margins and higher radical prostatectomy Gleason score. Total and index tumor extent was significantly associated with time to biochemical recurrence in Kaplan-Meier estimates. Total and index tumor extent significantly predicted shorter time to biochemical recurrence on univariate analysis but only index tumor extent was an independent predictor of time to biochemical recurrence on multivariate analysis. CONCLUSIONS: The study indicates that any tumor extent estimate in surgical specimens should be related to the dominant nodule (index tumor) and not to total tumor extent.