Post-MRI transrectal micro-ultrasonography of transition zone PI-RADS > 2 lesions for biopsy guidance.

OBJECTIVE: To prospectively determine the value of post-MRI micro-ultrasonography (microUS) in the diagnosis of transition zone (TZ) significant prostate cancer (sPCa). PATIENTS AND METHODS: Eighty-four consecutive men (66 ± 6.3 years) with a mean PSA level of 10.2 ± 7.4 ng/mL and at least one TZ-PI-RADS > 2 lesion were included. All patients had MRI-directed microUS and biopsy. Sensitivity and specificity of post-MRI microUS to visualize PI-RADS > 2 TZ lesions, the cancer detection rate of TZ-sPCa, and tumor characteristics according to their visibility on microUS were evaluated. Interreader agreement for detecting microUS+ lesions was evaluated using Cohen's kappa test. RESULTS: Of the 92 PI-RADS > 2 lesions, 71 (71/92; 77%) were visible on microUS and biopsy was performed without image fusion, which was required for the 21 invisible lesions (21/92; 22.8%). TZ-sPCa detection rate was 51.1% (47/92). Sensitivity and specificity of MRI-directed microUS were 83% (39/47; 95% CI: 69.2-92.4%) and 28.9% (13/45; 95% CI: 16.4-44.3%), on a per-lesion basis and 86.4% (38/45; 95% CI: 72.6-94.8%) and 27.5% (11/40; 95% CI: 14.6-43.9%) on a per-patient basis. Visible tumors on microUS exhibited a larger volume and a lower mean ADC value than non-visible tumors (15.8 ± 5.1 vs. 12.5 ± 3.6 mm and 0.82 ± 1.1 × 103 vs. 0.9 ± 1.4 × 10-3 mm2/s) (p = 0.02). Non-visible tumors showed a heterogeneous non-specific echotexture or were masked by the shadowing caused by corpora amylacea. Interreader agreement was almost perfect (kappa = 0.88; 95% CI: 0.79-0.95). The main limitation is the single-center feature of the study. CONCLUSION: MRI-targeted transrectal microUS is effective to detect TZ-sPCa. TRUS-MRI image fusion helps overcome limitations due to TZ tissue heterogeneity. KEY POINTS: microUS can visualize the majority of MRI-detected PI-RADS > 2 TZ lesions (sensitivity = 83%). Interreader agreement of MRI-directed microUS in the detection of TZ lesions appears excellent (kappa = 0.88). In 77% of PI-RADS > 2 TZ lesions, biopsy was performed under microUS visual control. MRI fusion system was only used to overcome limitations due to tissue heterogeneity of benign prostatic hyperplasia.

MRI-directed high-frequency (29MhZ) TRUS-guided biopsies: initial results of a single-center study.

OBJECTIVES: To evaluate the ability of high-frequency (29 MHz) transrectal micro-ultrasound (microUS) as a second-look examination after biparametric MRI (bp-MRI) and to reidentify focal lesions seen on diagnostic MRI and to detect new ones METHODS: A total of 118 consecutive men (mean age, 66 ± 13 [SD] years; range, 49-93 years) with a mean prostate-specific antigen level of 11 ± 19 (SD) ng/mL (range, 2-200 ng/mL) and at least one focal lesion (MRI+) with a score > 2 on bp-MRI were included. Of these, 79/118 (66.9%) were biopsy-naïve and 102/118 (86.5%) had non-suspicious rectal examination. All patients had MRI-directed microUS-guided biopsy using a 29-MHz transducer. All lesions visible on micro-ultrasound (microUS+) were targeted without image fusion, which was only used for MRI+/microUS- lesions. Significant prostate cancer (sPCa) was defined by a Gleason score ≥ 7 or a maximum cancer core length > 3 mm. RESULTS: A total of 144 focal prostatic lesions were analyzed, including 114 (114/144, 79.2%) MRI+/microUS+ lesions, 13 MRI+/microUS- lesions (13/144, 9%), and 17 MRI-/microUS+ lesions (17/144, 11.8%). Significant PCa was detected in 70 MRI+/microUS+ lesions (70/114, 61.4%), in no MRI+/microUS- lesion (0/13, 0%), and in 4 MRI-/microUS+ lesions (4/17, 23.5%). The sensitivity and specificity of microUS on a per-patient and a per-lesion basis were 100% (95% CI, 84.9-100%) and 22.8% (95% CI, 12.5-35.8%) and 100% (95% CI, 85.1-100%) and 22.6% (95% CI, 12.3-36.2%), respectively. CONCLUSION: MicroUS, as a second-look examination, may show promise to localize targets detected on bp-MRI. KEY POINTS: • Used as a second-look examination, microUS-guided biopsies have a 100% detection rate of sCa originating in the PZ or lower third of the TZ, without microUS-MRI image fusion. • MicroUS results may provide additional information about lesions visible on MRI. • MicroUS may provide the ability to detect small PZ lesions undetected by bp-MRI.

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.

In-Bore Transrectal MRI-Guided Biopsy With Robotic Assistance in the Diagnosis of Prostate Cancer: An Analysis of 57 Patients.

OBJECTIVE. The objective of our study was to analyze the feasibility and potential role of robotic-assisted transrectal MRI-guided biopsy for the diagnosis of prostate cancer. MATERIALS AND METHODS. A total of 57 patients (mean age, 67 ± 6 [SD] years; age range, 57-83 years; mean prostate-specific antigen level, 10.7 ± 6.1 ng/mL) with a single prostatic lesion visible on biparametric MRI (T2-weighted and DW images) underwent robotic-assisted MRI-guided transrectal biopsy. The procedure was analyzed in terms of technical success, defined by an accurate alignment of the needle guide with the lesion; occupation time of the MRI room; number of cores; cancer detection rate (CDR); and complications. RESULTS. The biparametric MRI score was 3, 4, and 5 in 11 (19%), 30 (53%), and 16 (28%) of the 57 patients, respectively. Twenty-three lesions (23/57, 40%) originated in the peripheral zone and 34 (34/57, 60%) in the transition zone. Software-based adjustments of the robot allowed the needle guide to be aligned with the target in all lesions. The number of cores was one, two, three, and four in one (2%), 36 (63%), 18 (32%), and three (5%) patients, respectively. Obtaining more than two cores had no incremental value in determining the Gleason score or the maximum cancer core length (MCCL). The overall CDR for any cancer was 67% (38/57). It was 95% (36/38) for tumors with Gleason grade of more than 3 or MCCL greater than 3 mm and 53% (20/38) for tumors with Gleason score greater than 6. No complications were observed. The median occupation time of the MRI room was 37.8 ± 9.7 minutes (range, 32-74 minutes). CONCLUSION. Robotic-assisted MRI-guided biopsy yields 100% technical success rate with a short MRI room occupation time and high CDRs using one or two cores.

Analysis of bladder cancer subtypes in neurogenic bladder tumors.

INTRODUCTION: To establish if the validated tumor biomarkers of luminal and basal bladder cancers in non neuro-urological patients are applicable to a neuro-urological population. MATERIALS AND METHODS: We retrieved bladder cancer samples from neuro-urological patients (n = 20) and non-neurological controls (n = 40). The expression of GATA3 and CK5/6 was analyzed using immunohistochemistry of microarray tissue sections. We also assessed the correlation between previous biomarker expression, gender, age, tumor stage (non-muscle-invasive bladder cancer (NMIBC)/muscle-invasive bladder cancer (MIBC)), squamous-cell differentiation and basal/luminal subtypes using Pearson's correlation coefficient (r). RESULTS: Mean age at diagnosis of bladder cancer in neuro-urological patients was 53.2 years (min 41-max 73). MIBC was found in 13 neuro-urological patients (65%). The luminal subtype was identified in 7 samples (35%, all urothelial differentiation). The basal subtype was found in 13 samples (65%): 12 squamous-cell and 1 sarcomatoid differentiation. GATA3 and CK5/6 were expressed in 6 (30%) neuro-urological patients. A significant positive correlation was found between GATA3 expression and the luminal subtype (p = 0.00001, r = 0.5676). This was not the case with the neuro-urological status (r = -0.307). A poor correlation was found between CK5/6 expression and the neuro-urological status (r = 0.471 and -0.471), squamous-cell differentiation (r = 0.092), tumor stage NMIBC/MIBC (r = -0.118 and 0.118) and basal/luminal subtypes (r = -0.157 and 0.194). CONCLUSION: In summary, the expression of GATA3 and CK5/6 could not differentiate the different subtypes of bladder cancer in neuro-urological patients. This implies that their specific histopathological signature is distinct from non neuro-urological patients. Additional pathways may be involved to explain their urothelial carcinogenesis mechanism.

Anti-inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia.

BACKGROUND: Permixon®, the hexanic lipidosterolic extract of saw palmetto Serenoa repens (LSESr), has shown properties that highlight its benefit in the management of benign prostate hyperplasia (BPH). To address its actual anti-inflammatory potency, we used a unique pro-inflammatory mouse model of prostate hyperplasia involving prostate-specific over-expression of prolactin transgene (Pb-Prl). METHODS: Six month-old Pb-Prl males were administered with Permixon® per os at the daily dose of 100 mg/kg for 28 days. Body and prostate weights were measured weekly and at sacrifice, respectively. Prostate histology was carefully assessed by a pathologist and detailed quantifications of epithelial and stromal compartments were performed using image analysis software. Luminal cell proliferation index was determined using Ki-67 immunostaining, and apoptosis using Bax/Bcl2 mRNA ratio. Tissue inflammation and fibrosis were assessed by histological analyses then quantified using CD45 immunostaining and picrosirius staining, respectively. Expression profiling of selected pro-inflammatory cytokines, chemokines, and chemokine receptors was performed by quantitative RT-PCR. RESULTS: In this model, Permixon® significantly decreased tissue weight and proliferation index specifically in the ventral lobe. Although treatment had no noticeable effect on epithelial histology of any lobe, it markedly reduced the histological hallmarks of inflammation in all lobes. This was confirmed by the global down-regulation of prostate pro-inflammatory cytokine profile, with significant reduction of CCR7, CXCL6, IL-6, and IL-17 expression. CONCLUSIONS: In this mouse model of prostate hyperplasia, Permixon® exerted potent anti-inflammatory properties in the whole prostate while anti-androgenic effects were lobe-specific, suggesting that distinct LSESr components may be involved in these effects. Our results support the beneficial role of Permixon® treatment for BPH. The relevance of CCR7, CXCL6, IL-6, and IL-17 as potential biomarkers to follow up BPH inflammatory status needs to be assessed.

Prolactin-induced prostate tumorigenesis links sustained Stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors.

Current androgen ablation therapies for prostate cancer are initially successful, but the frequent development of castration resistance urges the generation of alternative therapies and represents an important health concern. Prolactin/signal transducer and activator of transcription 5 (STAT5) signaling is emerging as a putative target for alternative treatment for prostate cancer. However, mechanistic data for its role in development or progression of prostate tumors are scarce. In vivo mouse studies found that local prolactin induced the amplification of prostate epithelial basal/stem cells. Because these cells are proposed cells of origin for prostate cancer and disease recurrence, we looked further into this amplification. Our results indicated that sustained Stat5 activation was associated with the occurrence of abnormal basal/stem cell clusters in prostate epithelium of prostate-specific prolactin-transgenic mice. Analysis of epithelial areas containing these clusters found high proliferation, Stat5 activation, and expression of stem cell antigen 1. Furthermore, enhanced prolactin signaling also led to amplification of a luminal cell population that was positive for stem cell antigen 1. These cells may originate from amplified basal/stem cells and might represent important progenitors for tumor development in prostate epithelium. These data provide a deeper understanding of the initial stages of prostate tumorigenesis induced by prolactin to help determine whether this hormone or its downstream messengers could be useful targets for prostate cancer treatment in the future.

Clear cell papillary renal cell carcinoma is an indolent and low-grade neoplasm with overexpression of cyclin-D1.

AIMS: Several entities have been individualized recently within the family of renal neoplasms with papillary features. Clear cell papillary renal cell carcinoma (CCPRCC) was first described in patients with end-stage renal disease, but is also observed in patients with normal renal function. The objective of this study was to document the clinicopathological and immunohistochemical characteristics of CCPRCC, with a special emphasis on cyclin D1 expression. METHODS AND RESULTS: The patients were 25 men and 17 women, mean age 60.7 years. Seventeen patients had a chronic renal disease. All tumours were stage pT1, with a mean diameter of 2 cm. Six tumours were multifocal. Tumours cells were mainly cuboidal, with clear cytoplasm and low-grade nuclei apically aligned. In all cases, Fuhrman nuclear grade was one or two. No necrosis or vascular invasion was seen. During follow-up (10-72 months), no metastasis or death related to the disease was observed. Immunohistochemistry showed strong and diffuse cytokeratin 7 immunoreactivity in all cases, but no labelling for AMACR or TFE3. There was diffuse nuclear cyclin D1 immunoreactivity in 83% of cases. CONCLUSION: CCPRCC is now a well-characterized entity. This tumour is an indolent and very low-grade neoplasm. Here we report the first study, to our knowledge, demonstrating the overexpression of cyclin D1 immunostaining by this tumour.

The reasons behind variation in Gleason grading of prostatic biopsies: areas of agreement and misconception among 266 European pathologists.

AIMS: The Gleason scoring system underwent revision at the International Society of Urological Pathology (ISUP) conference in 2005. It is not known how uropathologists have interpreted its recommendations. METHOD AND RESULTS: A web-based survey to European Network of Uropathology members received replies from 266 pathologists in 22 countries. Eighty-nine per cent claimed to follow ISUP recommendations. Key areas of disagreement included the following. Smoothly rounded cribriform glands were assigned Gleason pattern (GP) 3 by 51% and GP 4 by 49%. Necrosis was diagnosed as GP 5 by 62%. Any amount of secondary pattern of higher grade in needle biopsies was included in the Gleason score by 58%. Tertiary GP of higher grade on needle biopsies was included in the Gleason score by only 58%. If biopsy cores were embedded separately, only 56% would give a Gleason score for each core/slide examined; 68% would give a concluding Gleason score and the most common method was a global Gleason score (77%). Among those who blocked multiple biopsy cores together, 46% would only give an overall Gleason score for the case. CONCLUSION: Misinterpretation of ISUP 2005 is widespread, and may explain the variation in Gleason scoring seen. Clarity and uniformity in teaching ISUP 2005 recommendations is necessary.

Modulation of nerve-evoked contractions by ß3-adrenoceptor agonism in human and rat isolated urinary bladder.

Activation of ß3-adrenoceptors has been shown to have a direct relaxant effect on urinary bladder smooth muscle from both rats and humans, however there are very few studies investigating the effects of ß3-adrenoceptor agonists on nerve-evoked bladder contractions. Therefore in the current study, the role of ß3-adrenoceptors in modulating efferent neurotransmission was evaluated. The effects of ß3-adrenoceptor agonism on neurogenic contractions induced by electrical field stimulation (EFS) were compared with effects on contractions induced by exogenous acetylcholine (Ach) and αß-methylene adenosine triphosphate (αß-meATP) in order to determine the site of action. Isoproterenol inhibited EFS-induced neurogenic contractions of human bladder (pD2=6.79; Emax=65%). The effect of isoproterenol was selectively inhibited by the ß3-adrenoceptor antagonist L-748,337 (pKB=7.34). Contractions induced by exogenous Ach (0.5-1µM) were inhibited 25% by isoproterenol (3µM) while contractions to 10Hz in the same strip were inhibited 67%. The selective ß3-adrenoceptor agonist CL-316,243 inhibited EFS-induced neurogenic contractions of rat bladder (pD2=7.83; Emax=65%). The effects of CL-316,243 were inhibited in a concentration dependent manner by L-748,337 (pA2=6.42). Contractions induced by exogenous Ach and αß-meATP were significantly inhibited by CL-316,243, 29% and 40%, respectively. These results demonstrate that the activation of ß3-adrenoceptors inhibits neurogenic contractions of both rat and human urinary bladder. Contractions induced by exogenously applied parasympathetic neurotransmitters are also inhibited by ß3-agonism however the effect is clearly less than on neurogenic contractions (particularly in human), suggesting that in addition to a direct effect on smooth muscle, activation of prejunctional ß3-adrenoceptors may inhibit neurotransmitter release.

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.

Genetic variants of GPER/GPR30, a novel estrogen-related G protein receptor, are associated with human seminoma.

Testicular germ cell tumors (TGCTs) are the most common solid cancers in young men, with an increasing incidence over several years. However, their pathogenesis remains a matter of debate. Some epidemiological data suggest the involvement of both environmental and genetic factors. We reported two distinct effects of estrogens and/or xeno-estrogens on in vitro human seminoma-derived cells proliferation: (1) an antiproliferative effect via a classical estrogen receptor beta-dependent pathway, and (2) a promotive effect via a non-classical membrane G-protein-coupled receptor, GPR30/GPER, which is only overexpressed in seminomas, the most common TGCT. In order to explain this overexpression, we investigated the possible association of polymorphisms in the GPER gene by using allele-specific tetra-primer polymerase chain reaction performed on tissue samples from 150 paraffin-embedded TGCT specimens (131 seminomas, 19 non seminomas). Compared to control population, loss of homozygous ancestral genotype GG in two polymorphisms located in the promoter region of GPER (rs3808350 and rs3808351) was more frequent in seminomas but not in non-seminomas (respectively, OR = 1.960 (1.172-3.277) and 7.000 (2.747-17.840); p < 0.01). These polymorphisms may explain GPER overexpression and represent a genetic factor of susceptibility supporting the contribution of environmental GPER ligands in testicular carcinogenesis.

Primary urethral carcinoma: Recommendations of the oncology committee of the French Urology Association.

Primary urethral carcinoma (PUC) is defined as a tumor process arising within the urethra, with no history of other urinary tract localization or synchronous tumor of the urinary tract. The most common histological types are urothelial carcinoma (UC), squamous cell carcinoma (SCC) and adenocarcinoma (AC). In men, UC predominates, while AC is rare. In women, AC affects around one in two patients, while EC and UC are equally divided between the remaining cases. Diagnosis is often delayed, and requires endoscopic examination with biopsies. MRI is the gold standard for local staging. FDG-PET scan can help in cases of doubt about regional or distant extension. The prognosis remains unfavorable despite aggressive surgical treatment. Multimodal management combining surgery, radiotherapy and chemotherapy appears to improve prognosis in severe forms.

Expression of follicle-stimulating hormone receptor in tumor blood vessels.

BACKGROUND: In adult humans, the follicle-stimulating hormone (FSH) receptor is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. It is minimally expressed by the endothelial cells of gonadal blood vessels. METHODS: We used immunohistochemical and immunoblotting techniques involving four separate FSH-receptor-specific monoclonal antibodies that recognize different FSH receptor epitopes and in situ hybridization to detect FSH receptor in tissue samples from patients with a wide range of tumors. Immunoelectron microscopy was used to detect FSH receptor in mouse tumors. RESULTS: In all 1336 patients examined, FSH receptor was expressed by endothelial cells in tumors of all grades, including early T1 tumors. The tumors were located in the prostate, breast, colon, pancreas, urinary bladder, kidney, lung, liver, stomach, testis, and ovary. In specimens obtained during surgery performed to remove tumors, the FSH receptor was not expressed in the normal tissues located more than 10 mm from the tumors. The tumor lymphatic vessels did not express FSH receptor. The endothelial cells that expressed FSH receptor were located at the periphery of the tumors in a layer that was approximately 10 mm thick; this layer extended both into and outside of the tumor. Immunoelectron microscopy in mice with xenograft tumors, after perfusion with anti­FSH-receptor antibodies coupled to colloidal gold, showed that the FSH receptor is exposed on the luminal endothelial surface and can bind and internalize circulating ligands. CONCLUSIONS: FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of tumors. (Funded by INSERM.).

Standardization of Gleason grading among 337 European pathologists.

AIMS: The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7. METHODS AND RESULTS: Fifteen expert uropathologists reached two-thirds consensus on 15 prostate biopsies with GS 6-7 cancer. Eighty-five microphotographs were graded by 337 of 617 members of the European Network of Uropathology (ENUP), representing 19 countries. There was agreement between expert and majority member GS in 12 of 15 cases, while members upgraded in three cases. Among members and the expert consensus, a GS >6 was assigned by 64.5% and 60%, respectively. Mean member GS was higher than consensus GS in nine of 15 cases. A Gleason pattern (GP) 5 was reported by 0.3-5.6% in 10 cases. Agreement between consensus and member GS was 58.2-89.3% (mean 71.4%) in GS 6 cases and 46.3-63.8% (mean 56.4%) in GS 7 cases (P = 0.009). CONCLUSIONS: While undergrading of prostate cancer used to be prevalent, some now tend to overgrade. Minimum diagnostic criteria for GP 4 and 5 in biopsies need to be better defined. Image libraries reviewed by experts may be useful for standardization.

An interobserver reproducibility study on invasiveness of bladder cancer using virtual microscopy and heatmaps.

AIMS: The distinction between non-invasive (pTa) and invasive (pT1) non-muscle invasive bladder cancer (NMIBC) is subject to considerable interobserver variation. We aimed to generate a teaching set of images based on the diagnostic opinions of a panel of expert genitourinary pathologists. METHODS AND RESULTS: Twenty-five transurethral resection specimens initially reported as pT1 NMIBC from two university hospitals were selected on the basis of potential uncertainty of stromal invasion. Digitized slides were reviewed independently by a panel of eight genitourinary pathologists, who annotated any invasive area if present. Annotations were reviewed by the lead panel, and heatmaps of annotated areas were constructed. Reasons for discrepancies were analysed, and kappa scores were calculated to determine agreement among the eight panellists. Full agreement by the eight panellists was obtained in 11 of 25 cases (44%), with a multi-rater (Fleiss) kappa of 0.47 (P < 0.0001). After joint review of the seven discordant (agreement <75% of panellists) cases, consensus was obtained for six cases, and a teaching set of images was generated. CONCLUSIONS: Interobserver agreement among the panellists in the selected cases was moderate, but consensus could be reached in almost all cases. Heatmaps proved to be instrumental in generating a teaching set of images for standardization of histological criteria for NMIBC invasion.

Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases.

BACKGROUND: The Follicle Stimulating Hormone receptor (FSHR) is expressed by the vascular endothelium in a wide range of human tumors. It was not determined however if FSHR is present in metastases which are responsible for the terminal illness. METHODS: We used immunohistochemistry based on a highly FSHR-specific monoclonal antibody to detect FSHR in cancer metastases from 6 major tumor types (lung, breast, prostate, colon, kidney, and leiomyosarcoma ) to 6 frequent locations (bone, liver, lymph node, brain, lung, and pleura) of 209 patients. RESULTS: In 166 patients examined (79%), FSHR was expressed by blood vessels associated with metastatic tissue. FSHR-positive vessels were present in the interior of the tumors and some few millimeters outside, in the normally appearing tissue. In the interior of the metastases, the density of the FSHR-positive vessels was constant up to 7 mm, the maximum depth available in the analyzed sections. No significant differences were noticed between the density of FSHR-positive vessels inside vs. outside tumors for metastases from lung, breast, colon, and kidney cancers. In contrast, for prostate cancer metastases, the density of FSHR-positive vessels was about 3-fold higher at the exterior of the tumor compared to the interior. Among brain metastases, the density of FSHR-positive vessels was highest in lung and kidney cancer, and lowest in prostate and colon cancer. In metastases of breast cancer to the lung pleura, the percentage of blood vessels expressing FSHR was positively correlated with the progesterone receptor level, but not with either HER-2 or estrogen receptors. In normal tissues corresponding to the host organs for the analyzed metastases, obtained from patients not known to have cancer, FSHR staining was absent, with the exception of approx. 1% of the vessels in non tumoral temporal lobe epilepsy samples. CONCLUSION: FSHR is expressed by the endothelium of blood vessels in the majority of metastatic tumors.

[International Society of Urological Pathology (ISUP) Consensus Conference on handling and staging of radical prostatectomy specimens]. / Prise en charge de la pièce de prostatectomie radicale. Résultats de la conférence de consensus de la Société internationale d'uropathologie (ISUP).

The 2009 International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens issued recommendations for standardization of pathology reporting of radical prostatectomy specimens. The conference addressed specimen handling, T2 substaging, prostate cancer volume, extraprostatic extension, lymphovascular invasion, seminal vesicle invasion, lymph node metastases and surgical margins. This review summarizes the conclusions and recommendations resulting from the consensus process.

Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions.

Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.