The Diagnostic Yield and Concordance of Ureterorenoscopic Biopsies for Grading of Upper Tract Urothelial Carcinoma: A Dutch Nationwide Analysis.

Objectives: To evaluate the diagnostic yield and concordance of upper tract urothelial carcinoma (UTUC) grading between ureterorenoscopic biopsies and surgical resections. Materials and Methods: The nationwide Dutch Pathology Registry (nationwide network and registry of histo- and cytopathology in the Netherlands [PALGA]) was searched for UTUC-positive renal units (RUs) with histopathology excerpts from ureterorenoscopic biopsies and surgical resections, matched for laterality and localization of the tumor, from 2011 until 2018. The positive predictive value (concordance) of the biopsy grade with regard to the final grade according to the World Health Organization (WHO) 2004 classification was calculated. Results: A total of 1002 UTUC-positive rental units were included, of which 776 UTUC-positive RUs were graded according to the WHO 2004 classification in the ureterorenoscopic biopsy, the localization-matched surgical resection, or in both. The diagnostic yield of biopsies for a classifying diagnosis was 89% with a sensitivity for UTUC of 84%. In case of UTUC, the diagnostic yield for biopsy-based grading and staging was 97% and 72%, respectively. The concordance of high-grade biopsies with regard to the final histopathology was 97% and 62% for low-grade biopsies. Upgrading to final high grade occurred in 33% of the low-grade biopsies. Downgrading to final low grade occurred in 2% of high-grade biopsies. Conclusions: This is the first study to portray the limitations of ureterorenoscopic biopsies for UTUC in a nationwide cohort. The diagnostic yield of ureterorenoscopic biopsies for a classifying diagnosis is suboptimal, but the diagnostic yield for grading according to the WHO 2004 classification is high. Yet, a worrisome amount of ureterorenoscopic biopsies are upgraded with regard to the surgical resection. Consequently, one-third of patients, who qualify for kidney-sparing treatment according to one of the criteria recommended for risk stratification, might be stratified incorrectly. These findings stress the importance of a timely and stringent ureterorenoscopic follow-up after kidney-sparing surgery and highlight the need for improvements in the diagnostic approach to optimize the risk stratification.

Detection of clinically significant prostate cancer in biopsy-naïve men: direct comparison of systematic biopsy, multiparametric MRI- and contrast-ultrasound-dispersion imaging-targeted biopsy.

OBJECTIVES: To compare and evaluate a multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy (TBx) strategy, contrast-ultrasound-dispersion imaging (CUDI)-TBx strategy and systematic biopsy (SBx) strategy for the detection of clinically significant prostate cancer (csPCa) in biopsy-naïve men. PATIENTS AND METHODS: A prospective, single-centre paired diagnostic study included 150 biopsy-naïve men, from November 2015 to November 2018. All men underwent pre-biopsy mpMRI and CUDI followed by a 12-core SBx taken by an operator blinded from the imaging results. Men with suspicious lesions on mpMRI and/or CUDI also underwent MRI-TRUS fusion-TBx and/or cognitive CUDI-TBx after SBx by a second operator. A non-inferiority analysis of the mpMRI- and CUDI-TBx strategies in comparison with SBx for International Society of Urological Pathology Grade Group [GG] ≥2 PCa in any core with a non-inferiority margin of 1 percentage point was performed. Additional analyses for GG ≥2 PCa with cribriform growth pattern and/or intraductal carcinoma (CR/IDC), and GG ≥3 PCa were performed. Differences in detection rates were tested using McNemar's test with adjusted Wald confidence intervals. RESULTS: After enrolment of 150 men, an interim analysis was performed. Both the mpMRI- and CUDI-TBx strategies were inferior to SBx for GG ≥2 PCa detection and the study was stopped. SBx found significantly more GG ≥2 PCa: 39% (56/142), as compared with 29% (41/142) and 28% (40/142) for mpMRI-TBx and CUDI-TBx, respectively (P < 0.05). SBx found significantly more GG = 1 PCa: 14% (20/142) compared to 1% (two of 142) and 3% (four of 142) with mpMRI-TBx and CUDI-TBx, respectively (P < 0.05). Detection of GG ≥2 PCa with CR/IDC and GG ≥3 PCa did not differ significantly between the strategies. The mpMRI- and CUDI-TBx strategies were comparable in detection but the mpMRI-TBx strategy had less false-positive findings (18% vs 53%). CONCLUSIONS: In our study in biopsy-naïve men, the mpMRI- and CUDI-TBx strategies had comparable PCa detection rates, but the mpMRI-TBX strategy had the least false-positive findings. Both strategies were inferior to SBx for the detection of GG ≥2 PCa, despite reduced detection of insignificant GG = 1 PCa. Both strategies did not significantly differ from SBx for the detection of GG ≥2 PCa with CR/IDC and GG ≥3 PCa.

Validation of Confocal Laser Endomicroscopy Features of Bladder Cancer: The Next Step Towards Real-time Histologic Grading.

BACKGROUND: Cystoscopy enables the visualisation of suspicious bladder lesions but lacks the ability to provide real-time histopathologic information. Confocal laser endomicroscopy (CLE) is a probe-based optical technique that can provide real-time microscopic images. This high-resolution optical imaging technique may enable real-time tumour grading during cystoscopy. OBJECTIVE: To validate and adapt CLE criteria for bladder cancer diagnosis and grading. DESIGN, SETTING, AND PARTICIPANTS: Prospectively, 73 patients scheduled for transurethral resection of bladder tumour(s) were included. CLE imaging was performed intraoperatively prior to en bloc resection. Histopathology was the reference standard for comparison. INTERVENTION: Cystoscopic CLE imaging. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three independent observers evaluated the CLE images to classify tumours as low- or high-grade urothelial carcinoma (UC), or benign lesions. Interobserver agreement was calculated with Fleiss kappa analysis and diagnostic accuracy with 2×2 tables. RESULTS AND LIMITATIONS: Histopathology of 66 lesions (53 patients) revealed 25 low-grade UCs, 27 high-grade UCs, and 14 benign lesions. For low-grade UC, most common features were papillary configuration (100%), distinct cell borders (81%), presence of fibrovascular stalks (79%), cohesiveness of cells (77%), organised cell pattern (76%), and monomorphic cells (67%). A concordance between CLE-based classification and histopathology was found in 19 cases (76%). For high-grade UC, pleomorphic cells (77%), indistinct cell borders (77%), papillary configuration (67%), and disorganised cell pattern (60%) were the most common features. A concordance with histopathology was found in 19 cases (70%). In benign lesions, the most prevalent features were disorganised cell pattern (57%) and pleomorphic cells (52%), and a concordance with histopathology was found in four cases (29%). CONCLUSIONS: The CLE criteria enable identification of UC. CLE features correlate to histopathologic features that may enable real-time tumour grading. However, flat lesions remain difficult to classify. PATIENT SUMMARY: Confocal laser endomicroscopy may enable real-time cancer differentiation during cystoscopy, which is important for prognosis and disease management.

An In-vivo Prospective Study of the Diagnostic Yield and Accuracy of Optical Biopsy Compared with Conventional Renal Mass Biopsy for the Diagnosis of Renal Cell Carcinoma: The Interim Analysis.

BACKGROUND: Lack of accuracy in preoperative imaging leads to overtreatment of benign renal masses (RMs) or indolent renal cell carcinomas (RCCs). Optical coherence tomography (OCT) is real time and high resolution, enabling quantitative analysis through attenuation coefficient (µOCT, mm-1). OBJECTIVE: To determine the accuracy and diagnostic yield of OCT and renal mass biopsy (RMB) for the differentiation of benign RMs versus RCC and oncocytoma versus RCC. DESIGN, SETTING, AND PARTICIPANTS: From October 2013 to June 2016, 95 patients with solid enhancing RMs on cross-sectional imaging were prospectively included. All patients underwent subsequent excision or ablation. INTERVENTION: Percutaneous, image-guided, needle-based OCT followed by RMB in an outpatient setting under local anaesthesia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Accuracy and diagnostic yield, µOCT correlated to resection pathology or second biopsy during ablation. Tables (2×2) for RMB, receiver operating characteristic curve for OCT. Mann-Whitney test to differentiate µOCT of RMs. RESULTS AND LIMITATIONS: RMB diagnostic yield was 79% with sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of 100%, 89%, 99%, and 100%, respectively. Diagnostic yield and added value of OCT to differentiate RCC from benign was 99% and 15%, respectively. Significant difference was observed in median µOCT between benign RMs (3.2mm-1, interquartile range [IQR]: 2.65-4.35) and RCCs (4.3mm-1, IQR: 3.70-5.00), p=0.0171, and oncocytomas (3.38mm-1, IQR: 2.68-3.95) and RCCs (4.3mm-1, IQR: 3.70-5.00), p=0.0031. OCT showed sensitivity, specificity, positive predictive value. and NPV of 91%, 56%, 91%, and 56%, respectively, to differentiate benign RMs from RCCs and 92%, 67%, 95%, and 55%, respectively, to differentiate oncocytoma from RCC. Limitations include two reference standards and heterogeneity benign RMs. CONCLUSIONS: Compared with RMB, OCT has a higher diagnostic yield. OCT accurately distinguishes benign RMs from RCCs, and oncocytoma from RCCs, although specificity and NPV are lower. PATIENT SUMMARY: Optical coherence tomography, a new optical scan, exhibits similar sensitivity and positive predictive value than renal mass biopsy, although lower specificity and negative predictive value. Optical coherence tomography has a higher diagnostic yield for diagnosing renal cell carcinoma.

Association between gene expression profile of the primary tumor and chemotherapy response of metastatic breast cancer.

BACKGROUND: To better predict the likelihood of response to chemotherapy, we have conducted a study comparing the gene expression patterns of primary tumours with their corresponding response to systemic chemotherapy in the metastatic setting. METHODS: mRNA expression profiles of breast carcinomas of patients that later developed distant metastases were analyzed using supervised and non-supervised classification techniques to identify predictors of response to chemotherapy. The top differentially expressed genes between the responders and non-responders were identified and further explored. An independent dataset which was generated to predict response to neo-adjuvant CT was utilized for the purpose of validation. Response to chemotherapy was also correlated to the clinicopathologic characteristics, molecular subtypes, metastatic behavior and survival outcomes. RESULTS: Anthracycline containing regimens were the most common first line treatment (58.4%), followed by non-anthracycline/non-taxane containing (25.8%) and taxane containing (15.7%) regimens. Response was achieved in 41.6% of the patients to the first line CT and in 21.8% to second line CT. Response was not found to be significantly correlated to tumour type, grade, lymph node status, ER and PR status. Patients with HER2+ tumours showed better response to anthracycline containing therapy (p: 0.002). Response to first and second line chemotherapy did not differ among gene expression based molecular subtypes (p: 0.236 and p: 0.20). Using supervised classification, a 14 gene response classifier was identified. This 14-gene predictor could successfully predict the likelihood of better response to first and second line CT (p: <.0001 and p: 0.761, respectively) in the training set. However, the predictive value of this gene set in data of response to neoadjuvant chemotherapy could not be validated. CONCLUSIONS: To our knowledge, this is the first study revealing the relation between gene expression profiles of the primary tumours and their chemotherapy responsiveness in the metastatic setting. In contrast to the findings for neoadjuvant chemotherapy treatment, there was no association of molecular subtype with response to chemotherapy in the metastatic setting. Using supervised classification, we identified a classifier of chemotherapy response; however, we could not validate this classifier using neoadjuvant response data. TRIAL REGISTRATION: Non applicable. Subjects were retrospectively registered.

The role of desmoglein-3 in the diagnosis of squamous cell carcinoma of the lung.

Results from several microarray-based studies have led to the identification of up-regulated expression levels of the DSG3 gene in pulmonary squamous cell carcinomas (SQCCs). The purpose of this study was to determine the role of DSG3 expression in the diagnosis of SQCCs of the lung and to compare DSG3 with p63, CK5, and CK6, as markers of squamous cell differentiation. Expression of DSG3 mRNA was evaluated in bulk laser capture microdissection-derived microarray data and by quantitative reverse transcription PCR on both SQCCs and adenocarcinomas. Expression levels of p63, CK5, and CK6 were evaluated in microarray data from the same set. An immunohistochemical study using antibodies directed against DSG3, p63, and CK5/6 was also performed. DSG3 was over-expressed in SQCCs but had very limited expression in both adenocarcinomas and non-neoplastic lungs. The microarray data showed that DSG3 had a sensitivity and specificity of 88% and 98%, respectively, in detecting SQCC versus adenocarcinoma. In comparison, sensitivity and specificity was 92% and 82% for p63, and 85% and 96% for CK5, respectively. The correlation coefficient between the microarray and immunohistochemical data for these genes was greater than or equal to 0.9. Using immunohistochemistry, sensitivity and specificity of DSG3 for lung cancers were 98% and 99%, respectively. Therefore, DSG3 can be a useful ancillary marker to separate SQCC from other subtypes of lung cancer.