Clinical Applications of Immunohistochemistry in Germ Cell Tumors in Men.

Germ cell tumors (GCT) in men comprise of tumor subtypes with distinct histomorphologies, genetic and genomic alterations, and clinical behavior. Immunohistochemical (IHC) markers, including many newly described nuclear transcription factors, are often applied in challenging cases to arrive at a correct diagnosis and classification, and to establish germ cell origin for metastatic tumors. However, there is no established role for IHC markers in prognosis and therapy response prediction in GCTs. This chapter briefly reviews the clinical utility of IHC in diagnosis and classification of GCTs, including technical aspects of performing IHC and clinical applications of commonly used IHC markers in the workup of common and clinically relevant diagnostic scenarios.

Magnetic Resonance Imaging-guided In-bore and Magnetic Resonance Imaging-transrectal Ultrasound Fusion Targeted Prostate Biopsies: An Adjusted Comparison of Clinically Significant Prostate Cancer Detection Rate.

BACKGROUND: With the increasing adoption of targeted prostate biopsies, it becomes important to understand the strengths and shortcomings of the techniques available for targeting suspicious lesions. OBJECTIVE: To compare clinically significant prostate cancer (csPCa) detection rate with magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion versus in-bore biopsy in men with abnormal multiparametric MRI (mpMRI). DESIGN, SETTING, AND PARTICIPANTS: This single-center, retrospective analysis of prospectively generated data included all men with abnormal mpMRI and fusion or in-bore biopsy between May 2017 and April 2018. Grade group (GG) 2-5 cancers were considered csPCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Detection of csPCa was adjusted according to patient- and lesion-related characteristics using propensity score weighting. Secondary endpoints included the detection of clinically insignificant tumors and the rate of GG upgrade from biopsy to prostatectomy specimen. Analyses were performed at patient and lesion levels. RESULTS AND LIMITATIONS: A total of 103 and 300 men were included in the in-bore and fusion cohorts, respectively. On a per-patient basis, in-bore biopsies detected a higher proportion of csPCa (61%, 63/103) than fusion plus systematic biopsies (47%, 141/300; adjusted odds ratio [OR]: 2.1, 95% confidence interval [CI]: 1.6-2.8, p<0.0001). In-bore biopsies also detected fewer (11%, 11/103) clinically insignificant cancers than fusion biopsies (18%, 53/300; OR: 0.5, 95% CI: 0.3-0.8, p=0.001). Of those who had radical prostatectomy, GG upgrade after surgery was seen in 17% (4/24) of the men in the in-bore cohort and in 27% (22/82) of the men in the fusion cohort (p=0.55). CONCLUSIONS: MRI-guided in-bore biopsies detected more clinically significant and fewer insignificant prostate cancers than MRI-TRUS fusion targeted biopsies. Further cost-utility and patient outcome analyses are needed. PATIENT SUMMARY: In-bore biopsies (where the patient is on the magnetic resonance imaging [MRI] scanner itself) detected more aggressive cancers and fewer indolent cancers than fusion (where software blends MRI and ultrasound images) biopsies. These findings may help patients and physicians choose the best biopsy approach.

Molecular Subtyping of Clinically Localized Urothelial Carcinoma Reveals Lower Rates of Pathological Upstaging at Radical Cystectomy Among Luminal Tumors.

BACKGROUND: Upstaging of clinical T1-T2 urothelial carcinoma (UC) to non-organ-confined (NOC) pathological stage ≥T3 or N+ at radical cystectomy (RC) is common. Tools for stratifying patients who may have NOC disease are limited. OBJECTIVE: To determine an association of a genomic subtyping classifier (GSC) with pathological upstaging in multi-institutional cohort of patients with cT1-T2 UC treated with RC. DESIGN, SETTING, AND PARTICIPANTS: Precystectomy transurethral specimens from 206 patients with high-grade, cT1-T2, N0M0 UC, who underwent RC without neoadjuvant chemotherapy, underwent GSC testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Uni- and multivariable logistic regression analyses evaluated GSC for upstaging, defined as pT3/T4 and/or pTanyN1-3 disease at RC. RESULTS AND LIMITATIONS: Pathological upstaging occurred in 23% of cT1 and 57% of cT2 cases. Lower rates of upstaging to NOC was seen for luminal versus nonluminal tumors (34% vs 51%, p=0.02). The differences in upstaging were confined to T stage, with no difference in node positivity for luminal versus nonluminal patients (cT1: 13% for both [p>0.9], cT2: 15% and 23% [p=0.6], respectively). Fewer patients with luminal tumors were upstaged to ≥pT3Nany compared with nonluminal tumors (Mantel-Haenszel p=0.002; cT1: 13% vs 30%, cT2: 34% vs 58%). On multivariable logistic regression analysis, nonluminal patients were more likely to be upstaged to ≥pT3 at RC (p<0.001). Limitations include retrospective design and sample size. CONCLUSIONS: Molecular subtyping of clinically localized UC demonstrated that luminal tumors have lower rates of upstaging to non-organ-confined disease compared with nonluminal tumors. If validated, these data can help inform which patients may need multimodal therapy. PATIENT SUMMARY: Determining whether bladder cancer has spread beyond the bladder is challenging at diagnosis. In this paper, genomics helped identify patients who were more likely to have aggressive disease that has spread outside the bladder. These patients may benefit from chemotherapy prior to surgery.

Diagnostic Performance of Prospectively Assigned Likert Scale Scores to Determine Extraprostatic Extension and Seminal Vesicle Invasion With Multiparametric MRI of the Prostate.

OBJECTIVE: The objective of this study was to determine the diagnostic performance of a prospectively assigned 5-point Likert scale for determination of extraprostatic extension (EPE) and seminal vesicle invasion (SVI). MATERIALS AND METHODS: This study was a single-center, retrospective analysis of prospectively collected data including all men with abnormal 3-T multiparametric MRI and subsequent radical prostatectomy between November 1, 2016, and September 30, 2017. Scores from a 5-point subjective Likert scale (1 = highly unlikely, 5 = highly likely) for the likelihood of EPE and SVI were prospectively assigned during clinical MRI interpretation. EPE and SVI status at whole-mount prostatectomy specimen served as the standard of reference. RESULTS: Among the 89 eligible men, whole-mount histopathology revealed organ-confined prostate cancer, EPE, and SVI in 49% (44/89), 46% (41/89), and 18% (16/89) of patients, respectively. Of the pathologically proven cases of EPE, 18% (2/11), 17% (4/24), 65% (17/26), 46% (6/13) and 80% (12/15) were assigned Likert scores of 1-5, respectively. Of the pathologically proven cases of SVI, 5% (3/58), 11% (2/18), 66% (2/3), 66% (2/3) and 100% (7/7) were assigned Likert scores of 1-5, respectively. The positive predictive values for scores of 4 or 5 were 64% for EPE and 90% for SVI. The negative predictive values for scores of 1 or 2 were 87% for EPE and 93% for SVI. Likert scores for EPE (odds ratio, 2.1; 95% CI, 1.3-3.4) and for SVI (odds ratio, 4.7; 95% CI, 2.3-9.6) were both associated with EPE and SVI on multivariate analysis. CONCLUSION: A 5-point Likert scale can effectively convey the degree of suspicion of EPE and SVI on multiparametric MRI of the prostate, facilitating informed decision-making.

Prospective Inclusion of Apparent Diffusion Coefficients in Multiparametric Prostate MRI Structured Reports: Discrimination of Clinically Insignificant and Significant Cancers.

OBJECTIVE: The purpose of this study was to assess the diagnostic performance of prospectively assigned mean apparent diffusion coefficient (ADC) values in multiparametric MRI (mpMRI) structured reports for discriminating clinically insignificant (International Society of Urological Pathology [ISUP] group 1) from clinically significant (ISUP groups 2-5) prostate cancer. MATERIALS AND METHODS: This single-center study included men with abnormal 3-T mpMRI findings (Prostate Imaging Reporting and Data System version 2 score, ≥ 3) who subsequently underwent radical prostatectomy or targeted biopsy with positive results. One of nine radiologists prospectively reported the mean ADC for each lesion during clinical interpretation. Lesions with ADC ≤ 0.700 mm2/s × 10-3 were flagged as concerning for clinically significant prostate cancer. The index lesion at MRI correlated with the site-concordant lesion at targeted biopsy or whole-mount histopathologic analysis. Logistic regression was used to evaluate the utility of mean ADC values for discriminating ISUP grade group 1 from groups 2-5. Diagnostic performance was assessed by ROC AUC. RESULTS: Among the 218 eligible men, those with ISUP group 2-5 lesions had lower mean ADC values than those with ISUP 1 lesions; overall, 0.598 vs 0.803 mm/s2 × 10-3 (p < 0.0001); peripheral zone (PZ), 0.597 vs 0.855 mm/s2 × 10-3 (p < 0.0001); transition zone (TZ), 0.600 vs 0.660 mm/s2 × 10-3 (p = 0.035). The AUC for the PZ was 0.91 and for the TZ was 0.70. The optimal ADC cutoff values were 0.682 mm/s2 × 10-3 for PZ lesions and 0.638 mm2/s × 10-3 for TZ lesions, resulting in sensitivity and specificity of 78% and 94% for the PZ and 72% and 67% for the TZ. CONCLUSION: ADC values estimated prospectively in a clinical setting can help differentiate clinically insignificant from clinically significant prostate cancer, facilitating prebiopsy and pretreatment risk stratification.

Optimal sampling scheme in men with abnormal multiparametric MRI undergoing MRI-TRUS fusion prostate biopsy.

OBJECTIVES: To determine the implications of different prostate sampling schemes on the diagnosis of clinically significant prostate cancer (csPCA, ISUP group 2-5) and clinically insignificant prostate cancer (ciPCA, ISUP group 1) in men with abnormal multiparametric magnetic resonance imaging (mpMRI) undergoing MRI-transrectal ulrasound fusion targeted biopsies. MATERIALS AND METHODS: This is a retrospective analysis of a cohort including all men who had a single lesion on mpMRI of the prostate performed between January 2016 and June 2017. All men underwent an MRI-transrectal ulrasound fusion biopsy and systematic (SBx) sampling of the prostate, which combined and were considered the standard of reference. The hypothetical 3 biopsy sampling schemes were defined as follows: Targeted biopsy only (TBx), TBx + ipsilateral SBx (ipsi-SBx) and TBx + contralateral SBx (contra-SBx) and were evaluated for the detection of csPCA and ciPCA. Sensitivity and 95% intervals were calculated, McNemar test was used to compare sensitivities between the various sampling schemes. RESULTS: TBx + SBx detected csPCa in 47% (55 of 116) of the 116 men who met eligibility criteria. Sensitivity and 95% confidence intervals for csPCa detection was 85.5% (73.3%-93.5%), 96.4% (87.5%-99.6%), and 92.7 (82.4%-98%) for TBx alone, TBx + ipsi-SBx and TBx + contra-SBx, respectively. csPCa detection rates were higher for both TBx + ipsi-SBx and TBx + contra-SBx compared to TBx alone. Clinically insignificant cancers alone were detected in 7.7% (9 of 116), 10.3% (12 of 116), and 14.6% (17 of 116) of the cohort by TBx only and TBx + ipsi-SBx, and TBx + contra-SBx, respectively. CONCLUSIONS: TBx + ipsi-SBx may increase the detection of csPCa while limiting overdiagnosis of indolent cancers.

Case 258: Granulomatous Prostatitis.

History A 68-year-old man with a remote history of a previously resected high-grade urothelial carcinoma in the renal pelvis was being observed and was undergoing urologic treatment for recurrent low-grade urothelial carcinoma of the bladder. During his most recent evaluation, he reported no specific symptoms and denied experiencing hematuria, dysuria, or abdominal pain. At routine surveillance MRI of the abdomen and pelvis (images not shown), a lesion was noted in the peripheral zone of the prostate gland. The prostate-specific antigen level was elevated (7.51 ng/mL [normal range, 0.00-4.00 ng/mL]). The patient had no family history of prostate cancer and had never undergone prostate biopsy. MRI of the prostate with an endorectal coil was subsequently performed.

Reproducibility of Index Lesion Size and Mean Apparent Diffusion Coefficient Values Measured by Prostate Multiparametric MRI: Correlation With Whole-Mount Sectioning of Specimens.

OBJECTIVE: The purpose of this study is to determine the intra- and interreader agreement for index lesion size and mean apparent diffusion coefficient (ADC) value measurements performed by five readers using whole-mount histopathologic specimens processed with a patient-specific, MRI-based, 3D-printed mold as the standard of reference. MATERIALS AND METHODS: All men who underwent multiparametric MRI of the prostate performed using a 3-T scanner with endorectal and phased-array surface coils, followed by prostatectomy conducted between November 2015 and July 2016 at our institution, were identified. MRI examinations were independently reviewed by five readers with varying degrees of experience, two of whom had essentially no experience in prostate MRI interpretation before the study, to assess index lesion size and ADC values. A linear mixed model-based intraclass correlation was used to assess intra- and interreader reader agreement for lesion size and ADC measurements and agreement for size measurements between pathologic analysis and readers. RESULTS: A total of 80 men met the study eligibility criteria. Overall inter- and intrareader agreement for ADC measurements was excellent, with interclass correlation coefficient (ICC) values of 0.84 and 0.90, respectively; both inter- and intrareader agreement between experienced readers (0.82 and 0.92, respectively) and inexperienced readers (0.86 and 0.87, respectively) were excellent as well. The agreement between mean lesion size on imaging and histopathologic analysis ranged from poor (0.32) to good (0.66), with overall agreement considered fair (0.49). CONCLUSION: Readers with varying degrees of experience achieved good-to-excellent agreement for index lesion size and ADC values on multiparametric MRI of men with prostate cancer. This degree of reproducibility may improve preoperative risk stratification, informed decision making, and treatment planning for men with known or suspected prostate cancer.

Diagnostic Utility of a Likert Scale Versus Qualitative Descriptors and Length of Capsular Contact for Determining Extraprostatic Tumor Extension at Multiparametric Prostate MRI.

OBJECTIVE: The purpose of this study is to determine the reproducibility and diagnostic performance of a Likert scale in comparison with the European Society of Urogenital Radiology (ESUR) criteria and tumor-pseudocapsule contact length (TCL) for the detection of extraprostatic extension (EPE) at multiparametric MRI. MATERIALS AND METHODS: This was a retrospective review of all men who underwent multiparametric MRI followed by prostatectomy between November 2015 and July 2016. Multiparametric 3-T MRI studies with an endorectal coil were independently reviewed by five readers who assigned the likelihood of EPE using a 1-5 Likert score, ESUR criteria, and TCL (> 10 mm). EPE outcome (absent or present) for the index lesion at whole-mount histopathologic analysis was the standard of reference. Odds ratios (ORs) and areas under the ROC curve (Az) were used for diagnostic accuracy. The interreader agreement was determined using a weighted kappa coefficient. A p < 0.05 was considered significant. RESULTS: Eighty men met the eligibility criteria. At univariate analysis, the Likert score showed the strongest association (OR, 1.8) with EPE, followed by prostate-specific antigen level (OR, 1.7), ESUR score (OR, 1.6), and index lesion size (OR, 1.2). At multivariable analysis, higher Likert score (OR, 1.8) and prostate-specific antigen level (OR, 1.6-1.7) were independent predictors of EPE. The Az value for Likert scores was statistically significantly higher (0.79) than that for TCL (0.74; p < 0.01), but not statistically significantly higher than the value for ESUR scores (0.77; p = 0.17). Interreader agreement with Likert (κ = 0.52) and ESUR scores (κ = 0.55) was moderate and slightly superior to that for TCL (κ = 0.43). Except for TCL among inexperienced readers (κ = 0.34), reader experience did not affect interreader agreement. CONCLUSION: A Likert score conveying the degree of suspicion at multiparametric MRI is a stronger predictor of EPE than is either ESUR score or TCL and may facilitate informed decision making, patient counseling, and treatment planning.

Targeting phenotypic heterogeneity in benign prostatic hyperplasia.

Benign prostatic hyperplasia and associated lower urinary tract symptoms remain difficult to treat medically, resulting in hundreds of thousands of surgeries performed annually in elderly males. New therapies have not improved clinical outcomes since alpha blockers and 5 alpha reductase inhibitors were introduced in the 1990s. An underappreciated confounder to identifying novel targets is pathological heterogeneity. Individual patients display unique phenotypes, composed of distinct cell types. We have yet to develop a cellular or molecular understanding of these unique phenotypes, which has led to failure in developing targeted therapies for personalized medicine. This review covers the strategic experimental approach to unraveling the cellular pathogenesis of discrete BPH phenotypes and discusses how to incorporate these findings into the clinic to improve outcomes.

Incorporating Oxygen-Enhanced MRI into Multi-Parametric Assessment of Human Prostate Cancer.

Hypoxia is associated with prostate tumor aggressiveness, local recurrence, and biochemical failure. Magnetic resonance imaging (MRI) offers insight into tumor pathophysiology and recent reports have related transverse relaxation rate (R2*) and longitudinal relaxation rate (R1) measurements to tumor hypoxia. We have investigated the inclusion of oxygen-enhanced MRI for multi-parametric evaluation of tumor malignancy. Multi-parametric MRI sequences at 3 Tesla were evaluated in 10 patients to investigate hypoxia in prostate cancer prior to radical prostatectomy. Blood oxygen level dependent (BOLD), tissue oxygen level dependent (TOLD), dynamic contrast enhanced (DCE), and diffusion weighted imaging MRI were intercorrelated and compared with the Gleason score. The apparent diffusion coefficient (ADC) was significantly lower in tumor than normal prostate. Baseline R2* (BOLD-contrast) was significantly higher in tumor than normal prostate. Upon the oxygen breathing challenge, R2* decreased significantly in the tumor tissue, suggesting improved vascular oxygenation, however changes in R1 were minimal. R2* of contralateral normal prostate decreased in most cases upon oxygen challenge, although the differences were not significant. Moderate correlation was found between ADC and Gleason score. ADC and R2* were correlated and trends were found between Gleason score and R2*, as well as maximum-intensity-projection and area-under-the-curve calculated from DCE. Tumor ADC and R2* have been associated with tumor hypoxia, and thus the correlations are of particular interest. A multi-parametric approach including oxygen-enhanced MRI is feasible and promises further insights into the pathophysiological information of tumor microenvironment.

Molecular pathogenesis of human prostate basal cell hyperplasia.

BACKGROUND: Understanding the molecular pathogenesis of distinct phenotypes in human benign prostatic hyperplasia (BPH) is essential to improving therapeutic intervention. Current therapies target smooth muscle and luminal epithelia for relief of lower urinary tract symptoms (LUTS) due to BPH, but basal cell hyperplasia (BCH) remains untargeted. The incidence of has been reported at 8-10%, but a molecular and cellular characterization has not been performed on this phenotype. METHODS: Using freshly digested tissue from surgical specimens, we performed RNA-seq analysis of flow cytometry-purified basal epithelia from 3 patients with and 4 patients without a majority BCH phenotype. qPCR was performed on 28 genes identified as significant from 13 non-BCH and 7 BCH specimens to confirm transcriptomic analysis. IHC was performed on several non-BCH and BCH specimens for 3 proteins identified as significant by transcriptomic analysis. RESULTS: A total of 141 human BPH specimens were analyzed for the presence of BCH. Clinical characteristics of non-BCH and BCH cohorts revealed no significant differences in age, PSA, prostate volume, medical treatment, or comorbidities. Quantitation of cellular subsets by flow cytometry in 11 BCH patients vs. 11 non-BCH patients demonstrated a significant increase in the ratio of basal to luminal epithelia in patients with BCH (P <0.05), but no significant differences in the total number of leukocytes. RNA-seq data from flow cytometry isolated basal epithelia from patients with and without BCH were subjected to gene set enrichment analysis of differentially expressed genes, which revealed increased expression of members of the epidermal differentiation complex. Transcriptomic data were complemented by immunohistochemistry for members of the epidermal differentiation complex, revealing a morphological similarity to other stratified squamous epithelial layers. CONCLUSIONS: Increased expression of epidermal differentiation complex members and altered epithelial stratification resembles the progression of other metaplastic diseases. These data provide insight into the plasticity of the human prostate epithelium and suggest a classification of basal cell hyperplasia as a metaplasia.

Improved Magnetic Resonance Imaging-Pathology Correlation With Imaging-Derived, 3D-Printed, Patient-Specific Whole-Mount Molds of the Prostate.

OBJECTIVES: The aim of this study was to compare the anatomical registration of preoperative magnetic resonance imaging (MRI) and prostate whole-mount obtained with 3D-printed, patient-specific, MRI-derived molds (PSM) versus conventional whole-mount sectioning (WMS). MATERIALS AND METHODS: Based on an a priori power analysis, this institutional review board-approved study prospectively included 50 consecutive men who underwent 3 T multiparametric prostate MRI followed by radical prostatectomy. Two blinded and independent readers (R1 and R2) outlined the contours of the prostate, tumor, peripheral, and transition zones in the MRI scans using regions of interest. These were compared with the corresponding regions of interest from the whole-mounted histopathology, the reference standard, using PSM whole-mount results obtained in the study group (n = 25) or conventional WMS in the control group (n = 25). The spatial overlap across the MRI and histology data sets was calculated using the Dice similarity coefficient (DSC) for the prostate overall (DSCprostate), tumor (DSCtumor), peripheral (DSCPZ), and transition (DSCTZ) zone. Results in the study and control groups were compared using Wilcoxon rank sum test. RESULTS: The MRI histopathology anatomical registration for the prostate gland overall, tumor, peripheral, and transition zones were significantly superior with the use of PSMs (DSCs for R1: 0.95, 0.86, 0.84, and 0.89; for R2: 0.93, 0.75, 0.78, and 0.85, respectively) than with the use of standard WMS (R1: 0.85, 0.46, 0.66, and 0.69; R2: 0.85, 0.46, 0.66, and 0.69) (P < 0.0001). CONCLUSIONS: The use of PSMs for prostate specimen whole-mount sectioning provides significantly superior anatomical registration of in vivo multiparametric MRI and ex vivo prostate whole-mounts than conventional WMS.

Metastatic Melanoma to the Bladder: Case Report and Review of the Literature.

A 49-year-old Caucasian woman presented to the dermatology clinic for follow-up of malignant melanoma with a complaint of painless gross hematuria. Two years prior she was diagnosed with malignant melanoma from a skin lesion on her left flank treated with wide excision, negative axillary sentinel lymph node biopsy, and adjuvant radiotherapy. Subsequently, she had no evidence of disease until urologic evaluation of her hematuria revealed two lesions in her bladder and cytopathology demonstrated findings consistent with malignant melanoma. We review literature on melanoma metastatic to the bladder and discuss the potential role of metastasectomy and other treatment strategies in such rare cases.

An initial negative round of targeted biopsies in men with highly suspicious multiparametric magnetic resonance findings does not exclude clinically significant prostate cancer-Preliminary experience.

BACKGROUND: Targeted prostate biopsies are changing the landscape of prostate cancer (PCa) diagnosis with the degree of suspicion on multiparametric magnetic resonance imaging (mpMRI) being a strong predictor of targeted biopsy outcome. Data regarding the rate and potential causes of false-negative magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion-targeted biopsy in patients with highly suspicious mpMRI findings are lacking. OBJECTIVES: To determine the rate of clinically significant PCa detection in repeat targeted biopsy or surgery in patients with highly suspicious mpMRI findings and in an initial negative MRI-TRUS fusion-targeted biopsy. MATERIALS AND METHODS: In this single-center, retrospective study of prospectively generated data, men with highly suspicious lesions (Likert 5 score) on mpMRI and an initial negative MRI-TRUS fusion-targeted biopsy were reviewed. The rate of PCa detection in a subsequent MRI-TRUS fusion-targeted biopsy or radical prostatectomy was determined. Tumors in the intermediate- and high-risk groups according to the National Comprehensive Cancer Network criteria were considered clinically significant. RESULTS: A total of 32 men with 38 Likert 5 lesions were identified. Repeat targeted biopsy or surgery detected cancer in 42% (16/38) of the Likert 5 lesions with initial negative targeted biopsy. Most of these cancers were intermediate- (69%; 11/16) or high-risk (25%; 4/16) tumors. CONCLUSION: A negative round of targeted biopsies does not exclude clinically significant PCa in men with highly suspicious mpMRI findings. Patients with imaging-pathology disagreement should be carefully reviewed and considered for repeat biopsy or for strict surveillance.

Concordance in Biomarker Status Between Bladder Tumors at Time of Transurethral Resection and Subsequent Radical Cystectomy: Results of a 5-year Prospective Study.

PURPOSE: To assess the concordance rate in alterations of molecular markers at the time of transurethral resection (TUR) and subsequent radical cystectomy (RC) among patients with high-grade urothelial carcinoma of the bladder (UCB). METHODS: We prospectively performed immunohistochemical staining p53, p21, p27, Ki-67 and cyclin E1 on TUR and on RC specimens from 102 patients treated with RC and bilateral lymphadenectomy for high-grade UCB. We analyzed the concordance rate of individual markers and of the number of altered markers. Concordant and discordant findings were reported in the overall population and according to clinical stage. RESULTS: Median patient age was 74 years (IQR 67-79) and mostly male (86%). Median time from TUR to RC was 1.5 months (IQR 1.0-2.4). Clinical stage at time of RC was cTa/Tis/T1 in 50% , cT2 in 47% , and cT4 in 1% of patients Nine (9%) patients received neoadjuvant chemotherapy. The concordance of biomarkers between TUR and RC specimens was 92.2% , 77.5% , 80.4% , 77.5% , and 83.3% for cyclin E1, p21, p27, p53 and Ki-67, respectively. The concordance between number of altered biomarkers was 51.0%. CONCLUSIONS: The rate of individual marker alterations at time of TUR closely approximates that found at RC specimens. However, the correlation of number of altered markers is lower. Molecular marker status at TUR could help predict the marker status at RC and may help guide multimodal therapeutic planning.

Comparison of prostate cancer detection at 3-T MRI with and without an endorectal coil: A prospective, paired-patient study.

OBJECTIVES: To compare the sensitivity of 2 different non-endorectal coil strategies vs. endorectal coil (ERC) magnetic resonance imaging (MRI) for detection of prostate cancer (PCa). METHODS: In this prospective, single-center, paired-patient, paired-reader study, 49 men with a clinical indication for MRI underwent non-ERC (phased-array coil only) T2-weighted imaging and diffusion-weighted imaging followed by the same sequences using both ERC and phased-array coils (ERC Protocol). Patients were randomized into 1 of 2 arms: standard non-ERC protocol and augmented non-ERC protocol. Lesions with Likert score≥3 were defined as suspicious for cancer. Radical prostatectomy specimen or combined systematic plus targeted biopsies served as the standard of reference. Cancers were stratified into risk groups according to the National Comprehensive Cancer Network guidelines. Generalized estimating equations with Bonferroni correction were used for comparisons. The level of reader confidence was inferred by the Likert scores assigned to index lesions. RESULTS: The ERC protocol provided sensitivity (78%) superior to MRI without ERC for PCa detection, both with a standard (43%) (P<0.0001) or augmented (60%) (P<0.01) protocol. The ERC MRI missed less-intermediate or high-risk index lesions (4%) than standard non-ERC (42%) (P = 0.02) and augmented non-ERC MRI (25%), although the latter did not reach significance (P = 0.09). The ERC improved radiologist confidence for the detection of PCa (average Likert score = 4.2±1.4) compared to standard (2.3±2.3) and augmented (2.9±2.1) non-ERC (P = 0.001). CONCLUSIONS: The use of combined ERC and pelvic phased-array coil for T2-weighted imaging and diffusion-weighted imaging provides superior sensitivity for the detection of PCa compared to an examination performed without the ERC.

Assessment of Prospectively Assigned Likert Scores for Targeted Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsies in Patients with Suspected Prostate Cancer.

PURPOSE: We assess the performance of prospectively assigned magnetic resonance imaging based Likert scale scores for the detection of clinically significant prostate cancer, and analyze the pre-biopsy imaging variables associated with increased cancer detection using targeted magnetic resonance imaging-transrectal ultrasound fusion biopsy. MATERIALS AND METHODS: In this retrospective review of prospectively generated data including men with abnormal multiparametric prostate magnetic resonance imaging (at least 1 Likert score 3 or greater lesion) who underwent subsequent targeted magnetic resonance imaging-transrectal ultrasound fusion biopsy, we determined the association between different imaging variables (Likert score, lesion size, lesion location, prostate volume, radiologist experience) and targeted biopsy positivity rate. We also compared the detection of clinically significant cancer according to Likert scale scores. Tumors with high volume (50% or more of any core) Gleason score 3+4 or any tumor with greater Gleason score were considered clinically significant. Each lesion served as the elementary unit for analysis. We used logistic regression for univariate and multivariate (stepwise selection) analysis to assess for an association between targeted biopsy positivity rate and each tested variable. The relationship between Likert scale and Gleason score was evaluated using the Spearman correlation coefficient. RESULTS: A total of 161 men with 244 lesions met the study eligibility criteria. Targeted biopsies diagnosed cancer in 41% (66 of 161) of the men and 41% (99 of 244) of the lesions. The Likert score was the strongest predictor of targeted biopsy positivity (OR 3.7, p <0.0001). Other imaging findings associated with a higher targeted biopsy positivity rate included smaller prostate volume (OR 0.7, p <0.01), larger lesion size (OR 2.2, p <0.001) and anterior location (OR 2.0, p=0.01). On multiple logistic regression analysis Likert score, lesion size and prostate volume were significant predictors of targeted biopsy positivity. Higher Likert scores were also associated with increased detection of clinically significant tumors (p <0.0001). CONCLUSIONS: The Likert scale score used to convey the degree of suspicion on multiparametric magnetic resonance imaging is the strongest predictor of targeted biopsy positivity and of the presence of clinically significant tumor.

Association of overexpression of TIF1γ with colorectal carcinogenesis and advanced colorectal adenocarcinoma.

AIM: To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ), Smad4 and transforming growth factor-beta (TGFßR) across a spectrum representing colorectal cancer (CRC) development. METHODS: Tissue microarrays were prepared from archival paraffin embedded tissue, including 51 colorectal carcinomas, 25 tubular adenomas (TA) and 26 HPs, each with matched normal colonic epithelium. Immunohistochemistry was performed using antibodies against TIF1γ, Smad4 and TGFßRII. The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4). RESULTS: Overexpression of TIF1γ was detected in 5/26 (19%) HP; however, it was seen in a significantly higher proportion of neoplasms, 15/25 (60%) TAs and 24/51 (47%) CRCs (P < 0.05). Normal colonic mucosa, HP, and TAs showed strong Smad4 expression, while its expression was absent in 22/51 (43%) CRCs. Overexpression of TGFßRII was more commonly seen in neoplasms, 13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P < 0.05). Furthermore, there was a correlation between TIF1γ overexpression and Smad4 loss in CRC (Kendall tau rank correlation value = 0.35, P < 0.05). The levels of TIF1γ overexpression were significantly higher in stage III than in stage I and II CRC (P < 0.05). CONCLUSION: The findings suggest that over-expression of TIF1γ occurs in early stages of colorectal carcinogenesis, is inversely related with Smad4 loss, and may be a prognostic indicator for poor outcome.