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BACKGROUND: Screening for prostate cancer is burdened by a high rate of overdiagnosis. The most appropriate algorithm for population-based screening is unknown. METHODS: We invited 37,887 men who were 50 to 60 years of age to undergo regular prostate-specific antigen (PSA) screening. Participants with a PSA level of 3 ng per milliliter or higher underwent magnetic resonance imaging (MRI) of the prostate; one third of the participants were randomly assigned to a reference group that underwent systematic biopsy as well as targeted biopsy of suspicious lesions shown on MRI. The remaining participants were assigned to the experimental group and underwent MRI-targeted biopsy only. The primary outcome was clinically insignificant prostate cancer, defined as a Gleason score of 3+3. The secondary outcome was clinically significant prostate cancer, defined as a Gleason score of at least 3+4. Safety was also assessed. RESULTS: Of the men who were invited to undergo screening, 17,980 (47%) participated in the trial. A total of 66 of the 11,986 participants in the experimental group (0.6%) received a diagnosis of clinically insignificant prostate cancer, as compared with 72 of 5994 participants (1.2%) in the reference group, a difference of −0.7 percentage points (95% confidence interval [CI], −1.0 to −0.4; relative risk, 0.46; 95% CI, 0.33 to 0.64; P

Highlights • The lncRNA SCHLAP1 predicts poor prognosis in multifocal primary prostate cancer • Expression of SCHLAP1 is heterogeneous within and between different malignant foci • Multiple samples per patient is crucial, otherwise high SCHLAP1 may be overlooked • High SCHLAP1 is associated with reactive stroma and other aggressive features, In primary prostate cancer, the common multifocality and heterogeneity are major obstacles in finding robust prognostic tissue biomarkers. The long noncoding RNA SCHLAP1 has been suggested, but its prognostic value has not been investigated in the context of tumor heterogeneity. In the present study, expression of SCHLAP1 was investigated using real-time RT-PCR in a multisampled series of 778 tissue samples from radical prostatectomies of 164 prostate cancer patients (median follow-up time 7.4 y). The prognostic value of SCHLAP1 was evaluated with biochemical recurrence as endpoint. In total, 29% of patients were classified as having high expression of SCHLAP1 in at least one malignant sample. Among these, inter- and intrafocal heterogeneity was detected in 72% and 56%, respectively. High expression of SCHLAP1 was shown to be a predictor of biochemical recurrence in both uni- and multivariable cox regression analyses (P < 0.001 and P = 0.02). High expression of SCHLAP1 was also significantly associated with adverse clinicopathological characteristics, including grade group, high pT stage, invasive cribriform growth/intraductal carcinoma of the prostate, and reactive stroma. In conclusion, high expression of SCHLAP1 in at least one malignant sample is a robust prognostic biomarker in primary prostate cancer. For the first time, high SCHLAP1 expression has been associated with the aggressive histopathologic feature reactive stroma. The expression of SCHLAP1 is highly heterogeneous, and analysis of multiple samples is therefore crucial in determination of the SCHLAP1 status of a patient.

Primary prostate cancer shows a striking intraorgan molecular heterogeneity, with multiple spatially separated malignant foci in the majority of patients. Metastatic prostate cancer, however, typically reveals more homogenous molecular profiles, suggesting a monoclonal origin of the metastatic lesions. Longitudinal mutational spectra, comparing multiple primary lesions with metastases from the same patients remain poorly defined. We have here analyzed somatic mutations in multisampled, spatio-temporal biobanked lesions (38 samples from primary foci and 1 sample from each of 8 metastases from seven prostate cancer patients) applying a custom-designed panel targeting 68 prostate cancer relevant genes. The metastatic samples were taken at time of primary surgery and up to 7 years later, and sampling included circulating tumor DNA in plasma or solid metastatic tissue samples. A total of 282 somatic mutations were detected, with a range of 0 to 25 mutations per sample. Although seven samples had solely private mutations, the remaining 39 samples had both private and shared mutations. Seventy-four percent of mutations in metastases were not found in any primary samples, and vice versa, 96% of mutations in primary cancers were not found in any metastatic samples. However, for three patients, shared mutations were found suggesting the focus of origin, including mutations in AKT1, FOXA1, HOXB13, RB1 and TP53. In conclusion, the spatio-temporal heterogeneous nature of multifocal disease is emphasized in our study, and underlines the importance of testing a recent sample in genomics-based precision medicine for metastatic prostate cancer.

The majority of prostate cancer patients are diagnosed with multiple primary malignant foci. The distinct foci are exceptionally heterogeneous with regard to DNA mutations, but whether this is recapitulated at the transcriptome level remains unknown. In this study, inter- and intrafocal heterogeneity has been assessed by whole-transcriptome sequencing of 87 tissue samples from 23 patients with localized prostate cancer treated with radical prostatectomy. From each patient, multiple samples were taken from one or more malignant foci, in addition to one sample from benign prostate tissue. Transcriptomic profiles of different malignant foci from the same patient showed a similar level of heterogeneity as tumors from different patients. This applies to expression of genes, fusion genes, and somatic mutations. Within-patient pair-wise analyses identified expression patterns linked to ETS status and extraprostatic extension. A set of 62 genes were found with low intrapatient heterogeneity and high interpatient heterogeneity, retaining stable expression profiles across foci within the same patient. Among these, 16 genes are associated with biochemical recurrence in a separately published study and are therefore nominated as biomarkers with prognostic value regardless of which malignant focus is sampled. In conclusion, an extensive heterogeneity in multifocal prostate cancer is confirmed at the gene expression level. Diagnostic biomarkers were identified for ETS positive samples and samples from extraprostatic extensions. Finally, prognostic biomarkers independent of multifocal heterogeneity were found.

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

Background Patients with high-risk prostate cancer (PC) can experience biochemical relapse (BCR), despite surgery, and develop noncurative disease. The present study aimed to reduce the risk of BCR with a personalized dendritic cell (DC) vaccine, given as adjuvant therapy, after robot-assisted laparoscopic prostatectomy (RALP). Methods Twelve weeks after RALP, 20 patients with high-risk PC and undetectable PSA received DC vaccinations for 3 years or until BCR. The primary endpoint was the time to BCR. The immune response was assessed 7 weeks after surgery (baseline) and at one-time point during the vaccination period. Results Among 20 patients, 11 were BCR-free over a median of 96 months (range: 84-99). The median time from the end of vaccinations to the last follow-up was 57 months (range: 45-60). Nine patients developed BCR, either during (n = 4) or after (n = 5) the vaccination period. Among five patients diagnosed with intraductal carcinoma, three experienced early BCR during the vaccination period. All patients that developed BCR remained in stable disease within a median of 99 months (range: 74-99). The baseline immune response was significantly associated with the immune response during the vaccination period (p = 0.015). For patients diagnosed with extraprostatic extension (EPE), time to BCR was longer in vaccine responders than in non-responders (p = 0.09). Among 12 patients with the International Society of Urological Pathology (ISUP) grade 5 PC, five achieved remission after 84 months, and all mounted immune responses. Conclusion Patients diagnosed with EPE and ISUP grade 5 PC were at particularly high risk of developing postsurgical BCR. In this subgroup, the vaccine response was related to a reduced BCR incidence. The vaccine was safe, without side effects. This adjuvant first-in-man Phase I/II DC vaccine study showed promising results. DC vaccines after curative surgery should be investigated further in a larger cohort of patients with high-risk PC.

Objective To provide population-based data on 10-year prostate cancer-specific mortality (PCSM), overall mortality (OM), treatment, and prognostic factors in patients with nonmetastatic prostate cancer (PCa). Materials and Methods Based on data from the Norwegian Prostate Cancer Registry, we calculated 10-year PCSM and OM in 3449 patients diagnosed with nonmetastatic PCa in 2004-2005 who underwent radical prostatectomy (n = 913), radiotherapy (n = 1334), or no local treatment (n = 1202). Patients were stratified according to risk group, Gleason grade group (GGG), and Eastern Cooperative Oncology Group (ECOG) performance status. Aalen-Johansen and Kaplan-Meier estimates and proportional hazards regressions were used. Results The 10-year PCSM rate was 8.5% (radical prostatectomy: 1.5, radiotherapy: 6.2%, no local treatment: 16.3%) and the OM rate was 25.5%. In the low-risk group, the risk of dying from other causes was 8-fold increased compared with death from PCa, the comparable factor being approximately 2 among high-risk patients. Patients with high-risk factors seemed to benefit the most from local treatment. Within each risk group, the 5 GGGs improved the prediction of PCSM. Having an ECOG performance status of ≥1 doubled the risk of PCSM compared with patients with an ECOG performance status of 0. Conclusion For all patients, the 10-year OM was about 3 times higher than PCSM, the greatest and lowest discrepancies emerging among patients with low- and high-risk tumors, respectively. The results support increased use of local treatment in high-risk patients. GGGs should be implemented in clinical practice. The role of ECOG performance status as prognostic factor has to be validated in future studies.

Introduction: Salvage robot-assisted radical prostatectomy (sRARP) is seen as an attractive option for salvage treatment of radiation therapy -recurrent prostate cancer (PC), thanks in part to the good visualisation that is possible using this modality. However, the results of fewer than 200 salvage sRARPs have been published in the literature. We report the outcomes in a cohort of initially high risk patients of robot-assisted radical prostatectomy as salvage local therapy for radiation-resistant PC in a Scandinavian healthcare setting. Materials and methods: A retrospective review of the charts of all patients who underwent sRARP for biochemical failure (BCF) after primary radiation treatment for localised PC at a single institution was performed. Results: Twenty-two patients, median age 67 years (range 57 to 72), had sRARP performed between June 2008 to July 2013. A median follow-up of 26 months (range 2 to 63) was observed. Perioperative complications occurred in 4 patients (18%), with one patient sustaining a rectal injury. Histo-pathological diagnosis was pT2 in three, pT3a in five, pT3b in twelve and pTx in one patient. Ten patients (45%) had a positive surgical margin (PSM). At follow-up, 54 % of patients were free of biochemical progression and 41% were continent. Conclusions: We showed that salvage RARP is technically feasible in a cohourt of patients with predominantly high risk disease. This study adds to the limited data already in the literature, demonstrating the high frequency of locally advanced (pT3b) PC, a patient group that is usually not included in salvage treatments, as e.g. high frequency ultrasound or salvage brachytherapy. Further, given that the historical barriers to salvage RP with higher rates of rectal injury and poor urinary control no longer seem to be applicable in the modern era, we think that more patients should be considered candidates for this potentially curative salvage treatment of radiation-resistant PC. However, long-term follow-up is needed to confirm if the additional burden on these patients confers to oncological control following the procedure.

BACKGROUND 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. MATERIALS AND METHODS 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. RESULTS 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

Prostate cancer is a highly heterogeneous disease and typically multiple distinct cancer foci are present at primary diagnosis. Molecular classification of prostate cancer can potentially aid the precision of diagnosis and treatment. A promising genomic classifier was published by The Cancer Genome Atlas (TCGA), successfully classifying 74% of primary prostate cancers into seven groups based on one cancer sample per patient. Here, we explore the clinical usefulness of this classification by testing the classifier’s performance in a multifocal context. We analyzed 106 cancer samples from 85 distinct cancer foci within 39 patients. By somatic mutation data from whole-exome sequencing and targeted qualitative and quantitative gene expression assays, 31% of the patients were uniquely classified into one of the seven TCGA classes. Further, different samples from the same focus had conflicting classification in 12% of the foci. In conclusion, the level of both intra- and interfocal heterogeneity is extensive and must be taken into consideration in the development of clinically useful molecular classification of primary prostate cancer.

BACKGROUND Previous studies suggest that lymphovascular invasion (LVI) has a weak and variable effect on prognosis. It is uncertain whether LVI, determined by diagnostic prostate biopsy, predicts prostate cancer death. Data from experimental studies have indicated that carcinoma-associated fibroblasts in the reactive stroma could promote LVI and progression to metastasis. Thus, combining LVI with reactive stromal grade may identify prostate cancer patients at high risk of an unfavorable outcome. The purpose of the present study was to examine if LVI, determined by diagnostic biopsy, alone and in combination with reactive stromal grade could predict prostate cancer death. METHODS This population-based study included 283 patients with prostate cancer diagnosed by needle biopsy in Aust-Agder County (Norway) from 1991 to 1999. Clinical data were obtained by medical charts review. Two uropathologists evaluated LVI and reactive stromal grade. The endpoint was prostate cancer death. RESULTS Patients with LVI had marginally higher risk of prostate cancer death compared to patients without LVI (hazard ratio: 1.8, P-value = 0.04). LVI had a stronger effect on prostate cancer death risk when a high reactive stromal grade was present (hazard ratio: 16.0, P-value

B7-H3 and EpCAM are overexpressed in cancer and play a role in tumorigenesis and metastasis. In this study, the membranous, cytoplasmic and nuclear expression levels of B7-H3 and EpCAM biomarkers were mapped in three major subtypes of renal cell carcinoma (RCC). Expression of B7-H3 and EpCAM were evaluated using immunohistochemistry in RCC samples on tissue microarrays (TMAs), including clear cell RCCs (ccRCCs), type I and II papillary RCCs (pRCCs), and chromophobe RCCs (chRCCs). The association between B7-H3 and EpCAM expression and clinicopathological features as well as survival outcomes was determined. There was a statistically significant difference between B7-H3 and EpCAM expression among the different RCC subtypes. In ccRCC, higher cytoplasmic expression of B7-H3 was significantly associated with increase in nucleolar grade, lymph node invasion (LNI), invasion of the Gerota's fascia, and tumor necrosis, while no association was found with the membranous and nuclear expression. Moreover tumors with cytoplasmic expression of B7-H3 tended to have a worse prognosis for disease-specific survival (DSS) than those with membranous expression. In case of EpCAM, increased membranous expression of EpCAM was associated with nucleolar grade and tumor necrosis in ccRCC. Additionally, membranous EpCAM expression added prognostic value in patients with ccRCC who had high nucleolar grade versus low nucleolar grade. Moreover, membranous EpCAM expression was found to be an independent favorable prognostic marker for progression-free survival (PFS) in ccRCC. Our results demonstrated that higher cytoplasmic B7-H3 and membranous EpCAM expression are clinically significant in ccRCC and are associated with more aggressiveness tumor behavior.

BACKGROUND In vitro and in vivo studies have shown that nerves, tumor epithelium, and stroma interact and promote prostate cancer (PC) progression. Perineural invasion (PNI) is established amidst these interactions and may therefore indicate an aggressive PC phenotype. The purpose of the present study was to determine the relationship between PNI, tumor grade, reactive stroma, and PC-specific mortality. METHODS A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust–Agder County in the period of 1991–1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. Diagnostic prostate needle biopsies were reviewed with respect to presence of PNI, percentage of biopsy cores with PNI, Gleason score (GS), and reactive stromal grade (RSG). The endpoint was PC-specific mortality. RESULTS The presence of PNI was significantly associated with high tumor grade and abundant reactive stroma. The 10-year PC-specific survival for patients with and without PNI was 72% and 91%, respectively (P = 0.001, log rank). PNI predicted PC-specific mortality independently of clinical factors, though the effect of PNI was attenuated when adjusting for GS and RSG. However, a percentage of biopsy cores with PNI >50% was found to predict PC-specific mortality independently of other clinicopathologic parameters. CONCLUSIONS The present population-based study shows that PNI on diagnostic prostate needle biopsy is associated with increased risk of PC-specific mortality. Our findings demonstrate that the prognostic effect of PNI is dependent on an association with high grade carcinoma and reactive stroma. However; the impact of PNI on clinical outcome becomes stronger and independent of other clinicopathologic factors upon increased percentage of PNI positive biopsy cores. Thus, our study highlights the importance of PNI and microenvironmental interactions for the long-term outcome of PC. Prostate 76:207–214, 2016. © 2015 Wiley Periodicals, Inc.

BACKGROUND Reactive tumor stroma has been shown to play an active role in prostatic carcinogenesis. A grading system for reactive stroma in prostate cancer (PC) has recently been established and found to predict biochemical recurrence and prostate cancer-specific mortality (PCSM) in prostatectomized patients. To the best of our knowledge, there has been no study investigating the prognostic value of reactive stromal grading (RSG) with regard to PCSM when evaluated in diagnostic prostate needle biopsies. METHODS A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust–Agder County in the period 1991–1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. The endpoint was PCSM. RSG was evaluated on haematoxylin and eosin stained sections according to previously described criteria; grade 0, 0–5% reactive stroma; grade 1, 6–15%; grade 2, 16–50%; grade 3, 51–100%. RESULTS RSG could be evaluated in 278 patients. The median follow- up time was 110 months (interquartile range: 51–171). The 10-year PC - specific survival rate for RSGs of 0, 1, 2, and 3 was 96%, 81%, 69%, and 63%, respectively (P

Christian Beisland,1,2 Tom B Johannesen,3 Olbjorn Klepp,4 Ulrika Axcrona,5 Knut Martin Torgersen,6 Jan Kowalski,7 Oddvar Solli,6 Rickard Sandin,8 Jan Oldenburg9,10 1Department of Urology, Haukeland University Hospital, 2Department of Clinical Medicine, University of Bergen, Bergen, 3Department of Registration, Cancer Registry of Norway, Oslo, 4Department of Oncology, Ålesund Hospital, Ålesund, 5Department of Pathology, Oslo University Hospital, the Norwegian Radium Hospital, Oslo, 6Pfizer AS, Oslo, Norway; 7JK Biostatistics AB, Stockholm, 8Pfizer AB, Sollentuna, Sweden; 9Department of Oncology, Akershus University Hospital, Lørenskog, 10Medical Faculty, University of Oslo, Oslo, Norway Background: This population-wide retrospective, non-interventional registry study assessed changes in overall survival (OS) and factors influencing OS in Norwegian patients with renal cell carcinoma (RCC). Methods: Two population-wide health registries were used to identify all RCC patients with (mRCC) or without metastases diagnosed before (2002–2005) and after (2006–2008 and 2009–2011) introduction of targeted therapies. Median OS was estimated using Kaplan–Meier method. Cox proportional hazards regression modeling was used to identify prognostic factors. Results: Overall, 5,463 patients were diagnosed with RCC during 2002–2005 (n=1,898), 2006–2008 (n=1,631), and 2009–2011 (n=1,934); of these, 1,678 (31%) had mRCC. Patients diagnosed in 2009–2011 and 2006–2008 had significant (P

Objective: To establish predictors of clinical failure in patients operated with radical prostatectomy (RP) for clinically localized prostate cancer (PC) by analyzing the pathological characteristics of positive surgical margins (PSM). Patients and Methods: The RP specimens of 303 consecutive patients operated with RP between 1985 and 2009 were reviewed. PSM were analyzed with regard to the PSM length, location and multifocality and the Gleason score (GS) at the PSM. Results: Of the 163 patients with PSM, 79 (48%) progressed to clinical failure compared to 30 (22%) in the negative-margin-status group. In univariate analysis, a GS at the PSM ≥4 + 3 = 7 (p = 0. 013) and a PSM length >3.0 mm (p < 0.005) were significantly associated with higher clinical failure rates compared to a GS at the PSM ≤3 + 4 = 7 and ≤3.0 mm in extent, respectively. A linear extent of the PSM ≤3.0 mm appeared to have the same clinical outcome as in the group with a negative margin status. In multivariate analysis, a PSM length >3.0 mm remained an independent predictor of clinical failure. Conclusions: PSM length is an independent predictor of clinical failure following RP.

The classification working group of the International Society of Urological Pathology consensus conference on renal neoplasia was in charge of making recommendations regarding additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of the group performed an exhaustive literature review, assessed the results of the preconference survey and participated in the consensus conference discussion and polling activities. On the basis of the above inputs, there was consensus that 5 entities should be recognized as new distinct epithelial tumors within the classification system: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors. There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon that multicystic clear cell RCC is best considered as a neoplasm of low malignant potential. There was agreement that subtyping of papillary RCC is of value and that the oncocytic variant of papillary RCC should not be considered as a distinct entity. The hybrid oncocytic chromophobe tumor, which is an indolent tumor that occurs in 3 settings, namely Birt-Hogg-Dubé Syndrome, renal oncocytosis, and as a sporadic neoplasm, was placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, advances in our understanding of angiomyolipoma, including the epithelioid and epithelial cystic variants, were considered. In addition, the apparent relationship between cystic nephroma and mixed epithelial and stromal tumor was discussed, with the consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.

The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus, "the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

Previous studies suggest that lymphovascular invasion (LVI) has a weak and variable effect on prognosis. It is uncertain whether LVI, determined by diagnostic prostate biopsy, predicts prostate cancer death. Data from experimental studies have indicated that carcinoma-associated fibroblasts in the reactive stroma could promote LVI and progression to metastasis. Thus, combining LVI with reactive stromal grade may identify prostate cancer patients at high risk of an unfavorable outcome. The purpose of the present study was to examine if LVI, determined by diagnostic biopsy, alone and in combination with reactive stromal grade could predict prostate cancer death.This population-based study included 283 patients with prostate cancer diagnosed by needle biopsy in Aust-Agder County (Norway) from 1991 to 1999. Clinical data were obtained by medical charts review. Two uropathologists evaluated LVI and reactive stromal grade. The endpoint was prostate cancer death.Patients with LVI had marginally higher risk of prostate cancer death compared to patients without LVI (hazard ratio: 1.8, P-value = 0.04). LVI had a stronger effect on prostate cancer death risk when a high reactive stromal grade was present (hazard ratio: 16.0, P-value0.001). Therefore, patients with concomitant LVI and high reactive stromal grade were at particularly high risk for prostate cancer death.Evaluating LVI together with reactive stromal grade on diagnostic biopsies could be used to identify patients at high risk of death from prostate cancer. Prostate 76:1088-1094, 2016. © 2016 Wiley Periodicals, Inc.

Purpose To evaluate the probability of subsequent testicular cancer (STC) in patients with intratubular germ cell neoplasia unclassified (IGCNU) treated for first-time invasive germ cell cancer. Patients and Methods Sixty-one patients with germ cell testicular cancer or extragonadal germ cell cancer received follow-up from diagnosis of IGCNU to development of STC, initiation of IGCNU-definitive treatment (orchiectomy/radiotherapy), emigration, death, or end of follow-up. The probability of STC was assessed in subgroups according to chemotherapy burden. Results The probability of STC in the nonexposed patients was significantly increased compared with those exposed to chemotherapy (P = .05; 5-year probability of 54% [95% CI, 33% to 78%] and 23% [95% CI, 11% to 45%], respectively). In the group of patients treated with one to three cycles or no chemotherapy, the probability of STC was significantly increased compared with those exposed to four or more cycles (P = .03; 5-year probability of 42% [95% CI, 27% to 62%] and 22% [95% CI, 8% to 54%], respectively). Twenty-two of 22 patients were tumor-free and alive at a median of 56 months (range, 2 to 184 months) after diagnosis of STC. Conclusion Platinum-based chemotherapy may reduce the probability of STC in patients with IGCNU, particularly in those treated with four or more cycles of chemotherapy. A watch-and-wait strategy for patients with IGCNU may be justified in selected patients with future plans for paternity.

Prostate cancer patients diagnosed with high Gleason score (≥ 8) and large tumors (≥T2c) are considered high-risk patients and >50% will develop an early biochemical relapse following radical surgery. Presently, there is no curative therapy available for patients once when biochemical relapse occur. Based on encouraging clinical results from 6 relapsed prostate cancer patients treated under hospital exemption with dendritic cell (DC) vaccines we started an adjuvant, first in man, phase I/II study using autologous, monocyte derived DCs targeting autologous tumor antigens from primary tumor, combined with hTERT and survivin. Twenty patients were included in the study. All patients had pathological stage pT2-pT3b and Gleason score 7b-10. Following surgery prostate specific antigen (PSA) was < 0,2 µg/L in all patients. Fifteen patients have received 3-days DCs generated according to our standard protocol with a maturation cocktail composed of GM-CSF, IL-4, TNFα, IL1β and PgE2. Five patients were treated with a TLR 7/8 ligand containing maturation cocktail, resulting in DCs with a polarized release of IL-12p70 and no or low IL-10. The patients received 4 weekly vaccinations, then DTH vaccine at week 8 and thereafter-monthly vaccinations the first year, and every third month the second and third year. All patients except of two have completed vaccination. Of the 15 first patients using the standard DCs, three patients developed PSA relapse during vaccination (PSA measured twice >0,5 μg/L with minimum 4 weeks interval) and two additional patients relapsed after completed 3 years of vaccination. From the last 5 patients given the new type of DCs none have experienced PSA relapse. Seventy-five percent of the patients remain without biochemical relapse with a mean observation time of 47,5 (range 29-82) months. We confirm that the study is feasible and safe. Immune responses in the patients are under investigation. Altogether, our clinical results are promising and the use of adjuvant DC vaccines might become a new approach to prevent biochemical relapse in high-risk prostate cancer patients following radical surgery. Citation Format: Anne Merete Tryggestad, Iris Bigalke, Karol Axcrona, Bjørn Brennhovd, T Kirsti Hønnåshagen, Lisbeth Skoge, Lena Tjeldhorn, Lene Mowinckel, Stein Sæbøe-Larsen, Jens A L Jørgensen, Grete S Andreassen, Gjertrud Skorstad, Dag Josefsen, Ulrika Axcrona, Steinar Aamadal, Wolfgang Lilleby, Svein Dueland, Gunnar Kvalheim. A first in man phase I/II adjuvant dendritic cell vaccine study in high-risk prostate cancer patients following radical surgery reduce the incidence of biochemical relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT016.

Introduction Prostate cancer is the most common cancer type among men in the Western developed world. The majority of cases are multifocal, with several distinct tumours within the same gland. It is of particular interest to classify prostate cancer into different molecular subgroups to stratify it´s aggressiveness. Recently, The Cancer Genome Atlas (TCGA) proposed seven subtypes based on the expression of particular fusion genes or fusion gene partners, or mutation in particular genes. However, TCGA based their classification on a single sample per patient and did therefore not take the multifocal nature of the disease into account. We have therefore utilised the proposed subtypes on a large series of multifocal primary prostate cancers to understand the distribution and heterogeneity of subtypes within each prostate gland. Material and methods In this study, 153 tumour and benign samples from 41 prostatectomies performed between 2010 and 2012 at Oslo university hospital were selected. The samples represent 89 distinct tumour foci, with 2–3 included tumours per patient. All samples were analysed with high-coverage whole exome sequencing. Mutations relevant for the molecular classification were validated with PCR and Sanger sequencing. Expression levels and fusion transcripts were investigated in all samples with regular and real-time RT-PCR. Results and discussions Our results show both intra- and interfocal heterogeneity in the observed subtypes. For individual samples, 60% can be classified into one defined subtype. However, heterogeneity is observed in 47% of patients where tumours belong to more than one of the proposed subtypes. Investigating individual tumour foci, 53% belong to one subtype whereas the rest are classified into either multiple subtypes (12%) or do not harbour any of the molecular traits used in the proposed classification (35%). Interestingly, classification of samples into more than one subtype was mainly due to overexpression or fusion of multiple ETS-transcription factors (7%). Conclusion In this study, we observe a large degree of genomic dissonance both within and between tumour foci in the same prostate, resulting in heterogeneity in the classification of individual tumours. In fact, in 47% of the cases, patients can be classified into several subtypes, depending on which tumour the sample originates from. This heterogeneity greatly complicates the implementation of this particular classification in a clinical setting.

Reduced intercellular adhesion is implicated in the development of metastasis. This study investigates the expression of intercellular adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7) and their influence on survival in primary breast carcinomas and corresponding axillary lymph node metastases (ALNM), and evaluates associations between them and with clinicopathological factors. The expression of adhesion molecules was analyzed immunohistochemically in tissues from 196 patients with primary invasive breast carcinomas and their nodal metastases (174 ductal and 22 lobular types). The expression was evaluated using semi-quantitative scoring of the intensity and proportion of immunoreactivity. All five adhesion proteins showed significantly reduced expression in primary ductal carcinomas with re-expression in ALNM (p

In vitro and in vivo studies have shown that nerves, tumor epithelium, and stroma interact and promote prostate cancer (PC) progression. Perineural invasion (PNI) is established amidst these interactions and may therefore indicate an aggressive PC phenotype. The purpose of the present study was to determine the relationship between PNI, tumor grade, reactive stroma, and PC-specific mortality.A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust-Agder County in the period of 1991-1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. Diagnostic prostate needle biopsies were reviewed with respect to presence of PNI, percentage of biopsy cores with PNI, Gleason score (GS), and reactive stromal grade (RSG). The endpoint was PC-specific mortality.The presence of PNI was significantly associated with high tumor grade and abundant reactive stroma. The 10-year PC-specific survival for patients with and without PNI was 72% and 91%, respectively (P = 0.001, log rank). PNI predicted PC-specific mortality independently of clinical factors, though the effect of PNI was attenuated when adjusting for GS and RSG. However, a percentage of biopsy cores with PNI50% was found to predict PC-specific mortality independently of other clinicopathologic parameters.The present population-based study shows that PNI on diagnostic prostate needle biopsy is associated with increased risk of PC-specific mortality. Our findings demonstrate that the prognostic effect of PNI is dependent on an association with high grade carcinoma and reactive stroma. However; the impact of PNI on clinical outcome becomes stronger and independent of other clinicopathologic factors upon increased percentage of PNI positive biopsy cores. Thus, our study highlights the importance of PNI and microenvironmental interactions for the long-term outcome of PC.

Prostate cancer is the most common cancer type among men in the Western world. Most prostate cancers are multifocal with individual tumors harboring different aggressiveness. In recent genomics studies, the multifocal nature of prostate cancer has been investigated only in small sample cohorts. Here we have investigated the intra-organ mutational spectra of multiple tumors from a large cohort of prostate cancer patients. From radical prostatectomies performed between 2010 and 2012 at Oslo University Hospital, 43 prostatectomy specimens with multiple and clearly separated tumors were identified based on histology. From each of these prostatectomy specimens, DNA from frozen samples from 2-3 different tumor foci and corresponding normal tissue samples were analyzed by high-coverage whole-exome sequencing, adding up to a total of 159 samples. We identified 3093 somatic substitutions, insertions and deletions, with an average of 27 alterations per tumor sample. Both known and novel significantly mutated genes were identified and their distribution among different tumor foci from the same prostate was examined. Mutations in genes such as SPOP, MED12, and FOXA1 have previously been identified in prostate cancer and were also found to be frequently mutated in this cohort. However, the same mutations were rarely found in multiple tumor foci within the same prostate. In fact, for 13 out of the 43 examined patients there were no common mutations among tumors from the same prostate. For 12 patients, we found only one overlapping mutation among tumor foci. Whereas the overall list of mutated genes (n = 2101) overlap significantly with the 594 genes of the Cancer Gene Census (100/594; p=9.6e-06), this was not the case for 142 genes with overlapping mutations among different tumor foci (2/594; p=0.63). This indicates that the overlapping mutations are not typical cancer driving genes. To conclude, results from exome sequencing of multifocal prostate cancer show a large degree of heterogeneity in genomic alterations between different tumor foci within the same prostate. With very few common inter-foci mutations, an implementation of genome-based personalized prostate cancer medicine will require sampling of all tumor foci to tailor optimal treatment. Citation Format: Marthe Løvf, Sen Zhao, Ulrika Axcrona, Bjarne Johannesen, Andreas M. Hoff, Anne Cathrine Bakken, Kristina Totland Carm, Ola Myklebost, Leonardo A. Meza-Zepeda, Agnes K. Lie, Karol Axcrona, Ragnhild A. Lothe, Rolf I. Skotheim. Multifocal prostate cancer has high degree of genomic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1745. doi:10.1158/1538-7445.AM2017-1745

Reactive tumor stroma has been shown to play an active role in prostatic carcinogenesis. A grading system for reactive stroma in prostate cancer (PC) has recently been established and found to predict biochemical recurrence and prostate cancer-specific mortality (PCSM) in prostatectomized patients. To the best of our knowledge, there has been no study investigating the prognostic value of reactive stromal grading (RSG) with regard to PCSM when evaluated in diagnostic prostate needle biopsies.A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust-Agder County in the period 1991-1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. The endpoint was PCSM. RSG was evaluated on haematoxylin and eosin stained sections according to previously described criteria; grade 0, 0-5% reactive stroma; grade 1, 6-15%; grade 2, 16-50%; grade 3, 51-100%.RSG could be evaluated in 278 patients. The median follow- up time was 110 months (interquartile range: 51-171). The 10-year PC - specific survival rate for RSGs of 0, 1, 2, and 3 was 96%, 81%, 69%, and 63%, respectively (P 0.005). RSG remained independently associated with PCSM in a multivariate Cox regression analysis adjusting for prostate-specific antigen level, clinical stage, Gleason score, and mode of treatment. The concordance index of the multivariate model was 0.814 CONCLUSIONS: Our study demonstrates that RSG in diagnostic prostate needle biopsies predicts PCSM independently of other evaluable prognostic factors. Hence, RSG could be used in addition to traditional prognostic factors for prognostication and treatment stratification of PC patients.

We examined the distribution of CD1a⁺ cells and CD8⁺ and CD4⁺ T lymphocytes in prostate cancer (PCa) and correlated these with clinicopathological parameters. We also investigated whether the distribution of these cells was related to the expression of the cell membrane protein B7-H3, a putative negative regulator of the immune response expressed on PCa cells. A cohort of 151 PCa patients treated with radical prostatectomy (RP) was followed prospectively from 1985 until 2006 with a median follow-up of 9 years. Whole-mount sections of PCa specimens were immunostained to identify immune cells. A low number of CD1a⁺ cells was significantly associated with a high Gleason score and high pathological stage of pT3. The number of CD1a⁺ cells correlated significantly with the number of intratumoral and stromal CD8⁺ and stromal CD4⁺ lymphocytes. Kaplan-Meier analysis showed a tendency toward impaired biochemical progression-free survival in patients with few CD1a⁺ cells within their RP specimens. The expression of B7-H3 correlated inversely with the number of CD1a⁺ cells and intratumoral CD4⁺ lymphocytes; there was a trend for a similar inverse relationship between B7-H3 expression and the number of CD8⁺ lymphocytes.

Ethidium bromide (EtBr) is an intercalating agent, which binds tightly to mitochondrial DNA (mtDNA) during replication, and so blocks the function of mitochondria. EtBr inserts itself between the stacked bases in double-stranded DNA and specifically inhibits mtDNA transcription and replication by deleting RNA primers required for initiating mtDNA replication. In this study, the authors wanted to examine whether blocking mtDNA replication with EtBr could change the expression of stenmness genes and the expression of the immuneregulator B7-H3 in prostate cancer cell lines in vitro. Both PC-3 and DU145 prostate cancer cell lines were treated with 50 and 500 ng/mL of EtBr for 2 weeks. There was no difference in growth between EtBr-treated and control cells after 1 week. A slightly slower growth was observed for both cell lines during the second week of culture with EtBr compared to controls. After 2 weeks of culture with EtBr both cell lines showed increased expression of the stemness-related genes ABCG2, Oct3/4, Nanog1/Nanogp8, and CD44. Concomitantly, a dose-dependent increase of B7-H3 protein expression in both cell lines was identified and verified by both flow cytometry and immunocytochemistry. In conclusion, blocking mtDNA replication by EtBr induces increased expression of stemness genes, such as Oct3/4, Nanog, CD44, and ABCG2, in addition to the immune regulator B7-H3 in PC-3 and DU145 prostate cancer cell lines. The findings indicate that mitochondrial function may be associated with stemness of cancer cells and/or maintenance of a cancer stem cell phenotype. The finding of increased B7-H3 expression may be associated with the immunosuppression of cancer cells.

International audience; The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.

Prostate cancer patients diagnosed with high Gleason score (≥ 8) and large tumors (≥T2c) are considered high-risk patients and >50% will develop an early biochemical relapse. Presently, there is no curative therapy available for patients with biochemical relapse. Based on these findings we initiated in January 2011 a Phase I/II dendritic cell (DC) vaccine study. Patients included have pathological stage pT2 - pT3b, Gleason score 7b-10, pN0, pN+ or pNx and postoperative PSA < 0.2 μg/L. Following surgery autologous tumor cell lines were established from each patient using an in-house culturing method. mRNA from the tumor cell line was produced and used for DC vaccination in combination with mRNA hTERT and mRNA Survivin. DCs were differentiated from enriched monocytes, cultured for 2 days with IL4 and GM-CSF and matured with Jonuleit-maturation cocktail for 24 hours. The matured DCs were transfected separately with the 3 different mRNAs and then frozen and stored until use. The vaccination regimen includes one vaccine per week for four weeks, followed by monthly “vaccine boost” during the first year, then every 3 months the second and third year. Recently, a novel 3 days DC protocol using a TLR7/8-agonist maturation cocktail has been implemented at our department. Based on encouraging clinical results with this type of DCs in compassionate use patients with different types of tumors, we decided to change our DCs protocol to the new generation DCs. Of the 20 patients included in this trial 15 patients have been given the standard fast DCs and 5 have been vaccinated with the new type of DCs. 8 Patients given standard DC has completed 3 years of vaccination and 4 has completed 2 years of vaccination. 3 of 15 patient given standard DC has experienced PSA relapse during vaccination. None of the patients given the new type of DC has so far experienced raise in PSA levels. To our knowledge this is the first adjuvant DC vaccine study in high risk prostate cancer and we conclude that the study is feasible, safe and utmost promising. Extensive immune monitoring is ongoing taking advantage of the established autologous tumor cell lines from all patients. Citation Format: Anne Merete Aa. Tryggestad, Karol Axcrona, Iris Bigalke, Else M. Inderberg-Suso, Gjertrud Skorstad, Ulrika Axcrona, Steinar Aamdal, Gustav Gaudernack, Dolores Schendel, Wolfgang Lilleby, Svein Dueland, Gunnar Kvalheim. Clinical results of a Phase I/II trial of adjuvant therapeutic vaccination in high risk resected prostate cancer patients using autologous dendritic cells loaded with mRNA from primary prostate cancer tissue, hTERT and survivin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2235.