Tatjana Antic

Prostate Cancer: Differentiation of Central Gland Cancer from Benign Prostatic Hyperplasia by Using Diffusion-weighted and Dynamic Contrast-enhanced MR Imaging

PURPOSE To analyze the diffusion and perfusion parameters of central gland (CG) prostate cancer, stromal hyperplasia (SH), and glandular hyperplasia (GH) and to determine the role of these parameters in the differentiation of CG cancer from benign CG hyperplasia. MATERIALS AND METHODS In this institutional review board-approved (with waiver of informed consent), HIPAA-compliant study, 38 foci of carcinoma, 38 SH nodules, and 38 GH nodules in the CG were analyzed in 49 patients (26 with CG carcinoma) who underwent preoperative endorectal magnetic resonance (MR) imaging and radical prostatectomy. All carcinomas and hyperplastic foci on MR images were localized on the basis of histopathologic correlation. The apparent diffusion coefficient (ADC), the contrast agent transfer rate between blood and tissue (K(trans)), and extravascular extracellular fractional volume values for all carcinoma, SH, and GH foci were calculated. The mean, standard deviation, 95% confidence interval (CI), and range of each parameter were calculated. Receiver operating characteristic (ROC) and multivariate logistic regression analyses were performed for differentiation of CG cancer from SH and GH foci. RESULTS The average ADCs (× 10(-3) mm(2)/sec) were 1.05 (95% CI: 0.97, 1.11), 1.27 (95% CI: 1.20, 1.33), and 1.73 (95% CI: 1.64, 1.83), respectively, in CG carcinoma, SH foci, and GH foci and differed significantly, yielding areas under the ROC curve (AUCs) of 0.99 and 0.78, respectively, for differentiation of carcinoma from GH and SH. Perfusion parameters were similar in CG carcinomas and SH foci, with K(trans) yielding the greatest AUCs (0.75 and 0.58, respectively). Adding K(trans) to ADC in ROC analysis to differentiate CG carcinoma from SH increased sensitivity from 38% to 57% at 90% specificity without noticeably increasing the AUC (0.79). CONCLUSION ADCs differ significantly between CG carcinoma, SH, and GH, and the use of them can improve the differentiation of CG cancer from SH and GH. Combining K(trans) with ADC can potentially improve the detection of CG cancer. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100021/-/DC1.

Diffusion-Weighted and Dynamic Contrast-Enhanced MRI of Prostate Cancer: Correlation of Quantitative MR Parameters With Gleason Score and Tumor Angiogenesis

OBJECTIVE The objective of our study was to investigate whether quantitative parameters derived from diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) correlate with Gleason score and angiogenesis of prostate cancer. MATERIALS AND METHODS Seventy-three patients who underwent preoperative MRI and radical prostatectomy were included in our study. A radiologist and pathologist located the dominant tumor on the MR images based on histopathologic correlation. For each dominant tumor, the apparent diffusion coefficient (ADC) value and quantitative DCE-MRI parameters (i.e., contrast agent transfer rate between blood and tissue [K(trans)], extravascular extracellular fractional volume [v(e)], contrast agent backflux rate constant [k(ep)], and blood plasma fractional volume on a voxel-by-voxel basis [v(p)]) were calculated and the Gleason score was recorded. The mean blood vessel count, mean vessel area fraction, and vascular endothelial growth factor (VEGF) expression of the dominant tumor were determined using CD31, CD34, and VEGF antibody stains. Spearman correlation analysis between MR and histopathologic parameters was conducted. RESULTS The mean tumor diameter was 15.2 mm (range, 5-28 mm). Of the 73 prostate cancer tumors, five (6.8%) had a Gleason score of 6, 46 (63%) had a Gleason score of 7, and 22 (30.1%) had a Gleason score of greater than 7. ADC values showed a moderate negative correlation with Gleason score (r = -0.376, p = 0.001) but did not correlate with tumor angiogenesis parameters. Quantitative DCE-MRI parameters did not show a significant correlation with Gleason score or VEGF expression (p > 0.05). Mean blood vessel count and mean vessel area fraction parameters estimated from prostate cancer positively correlated with k(ep) (r = 0.440 and 0.453, respectively; p = 0.001 for both). CONCLUSION There is a moderate correlation between ADC values and Gleason score and between k(ep) and microvessel density of prostate cancer. Although the strength of the correlations is insufficient for immediate diagnostic utility, these results warrant further investigation on the potential of multiparametric MRI to facilitate noninvasive assessment of prostate cancer aggressiveness and angiogenesis.

Quantitative Analysis of Multiparametric Prostate MR Images: Differentiation between Prostate Cancer and Normal Tissue and Correlation with Gleason Score—A Computer-aided Diagnosis Development Study

PURPOSE To evaluate the potential utility of a number of parameters obtained at T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced multiparametric magnetic resonance (MR) imaging for computer-aided diagnosis (CAD) of prostate cancer and assessment of cancer aggressiveness. MATERIALS AND METHODS In this institutional review board-approved HIPAA-compliant study, multiparametric MR images were acquired with an endorectal coil in 48 patients with prostate cancer (median age, 62.5 years; age range, 44-73 years) who subsequently underwent prostatectomy. A radiologist and a pathologist identified 104 regions of interest (ROIs) (61 cancer ROIs, 43 normal ROIs) based on correlation of histologic and MR findings. The 10th percentile and average apparent diffusion coefficient (ADC) values, T2-weighted signal intensity histogram skewness, and Tofts K(trans) were analyzed, both individually and combined, via linear discriminant analysis, with receiver operating characteristic curve analysis with area under the curve (AUC) as figure of merit, to distinguish cancer foci from normal foci. Spearman rank-order correlation (ρ) was calculated between cancer foci Gleason score (GS) and image features. RESULTS AUC (maximum likelihood estimate ± standard error) values in the differentiation of prostate cancer from normal foci of 10th percentile ADC, average ADC, T2-weighted skewness, and K(trans) were 0.92 ± 0.03, 0.89 ± 0.03, 0.86 ± 0.04, and 0.69 ± 0.04, respectively. The combination of 10th percentile ADC, average ADC, and T2-weighted skewness yielded an AUC value for the same task of 0.95 ± 0.02. GS correlated moderately with 10th percentile ADC (ρ = -0.34, P = .008), average ADC (ρ = -0.30, P = .02), and K(trans) (ρ = 0.38, P = .004). CONCLUSION The combination of 10th percentile ADC, average ADC, and T2-weighted skewness with CAD is promising in the differentiation of prostate cancer from normal tissue. ADC image features and K(trans) moderately correlate with GS.

Mixed epithelial and stromal tumor of the kidney and cystic nephroma share overlapping features: reappraisal of 15 lesions.

CONTEXT Cystic nephroma is a rare cystic tumor, which only recently has been recognized as an exclusively adult lesion. Mixed epithelial and stromal tumor of the kidney is also a rare, recently recognized, biphasic tumor composed of tubular and cystic elements embedded in grossly recognizable spindle cell stroma. The histogenesis of both lesions is unclear. OBJECTIVES To compare clinical phenotype, morphology, and immunohistochemistry in mixed epithelial and stromal tumor of the kidney and cystic nephroma in order to explore the relationship between these 2 lesions. DESIGN Fifteen biphasic lesions (8 mixed epithelial and stromal tumors of the kidney and 7 cystic nephromas) were studied. All cases were reviewed and subjected to detailed pathologic studies, and the results were correlated with clinical findings. RESULTS Mixed epithelial and stromal tumor of the kidney occurred exclusively in women aged 36 to 80 years (mean, 49.7 years), all of whom had a history of estrogen therapy and/or obesity. Cystic nephroma occurred in both sexes; patients were aged 22 to 71 years (mean, 50.4 years), and a history of hormonal therapy was present on occasion. All 15 lesions were benign. Lesions varied by size, the proportion of cystic component, and the amount and cellularity of stroma. However, in all lesions tested, the stroma was diffusely positive for smooth muscle actin, and smooth muscle differentiation was confirmed by electron microscopy. In mixed epithelial and stromal tumors of the kidney, the stroma was positive for estrogen and progesterone receptors in 4 of 5 lesions tested. In cystic nephroma, focal positivity for hormone receptors was seen in 2 of 7 tumors tested; both positive lesions were from women. The epithelial lining in both mixed epithelial and stromal tumor of the kidney and cystic nephroma lesions was variable with regard to shape, cytoplasmic appearance, and immunophenotype (with focal positivity for CD10, cytokeratin 7, high-molecular-weight keratin, and Ulex europaeus detectable in both lesions). This pattern suggests variable differentiation, which was confirmed by electron microscopic studies (performed in 1 case). CONCLUSIONS While mixed epithelial and stromal tumor of the kidney has a strong association with the female sex and hormonal milieu, cystic nephroma can affect both sexes and, on occasion, may also have hormonal associations. Morphologically, there is considerable overlap between both lesions, which suggests that they may represent opposite ends of the spectrum of the same process. Our studies also suggest that the tubules may be entrapped rather than comprising an intrinsic component of the tumor. However, further studies, including molecular studies, are needed to support this hypothesis.

Seminal Vesicle Invasion in Prostate Cancer: Evaluation by Using Multiparametric Endorectal MR Imaging

PURPOSE To retrospectively evaluate the diagnostic performance of multiparametric endorectal magnetic resonance (MR) imaging, including T2-weighted, diffusion-weighted (DW), and dynamic contrast material-enhanced (DCE) MR techniques, for the diagnosis of seminal vesicle invasion (SVI) and to determine the incremental value of DW MR and DCE MR images. MATERIALS AND METHODS This retrospective HIPAA-compliant study was approved by the institutional review board, with a waiver of informed consent. The study included 131 patients (mean age, 68 years; range, 43-75 years) who underwent endorectal MR imaging before radical prostatectomy between January 2007 and April 2010. Two radiologists (A: experienced, B: less experienced) estimated the likelihood of SVI by using a five-point ordinal scale in three image-viewing settings: T2-weighted images alone; T2-weighted and DW MR images; and T2-weighted, DW MR, and DCE MR images. Sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) were calculated. Confidence intervals estimated with bootstrapping and the McNemar test or Fisher exact test were used to compare sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS Of the 131 patients, 23 (17.6%) had SVI identified after surgery. Review of T2-weighted MR images alone resulted in high specificity (93.1% and 93.6%, for radiologists A and B, respectively) and high negative predictive value (94.8% and 94.0%) but moderate sensitivity (59% and 52%) and positive predictive value (52% and 50%). Review of T2-weighted and DW MR images significantly improved specificity (96.6% [P = .02] and 98.3% [P = .003]) and positive predictive value (70% [P < .05] and 79% [P < .05]) without significantly improving AUC. Additional review of DCE MR images did not yield further incremental improvement. CONCLUSION Additional review of DW MR images improves specificity and positive predictive value in SVI detection compared with reviewing T2-weighted images alone. Addition of DCE MR images to this combination, however, does not provide incremental value for diagnosis of SVI.

Validation of Quantitative Analysis of Multiparametric Prostate MR Images for Prostate Cancer Detection and Aggressiveness Assessment: A Cross-Imager Study

PURPOSE To validate three previously identified quantitative image features across multiparametric magnetic resonance (MR) images acquired with imagers made by two different manufacturers to differentiate prostate cancer (PC) from normal prostatic tissue and to assess cancer aggressiveness. MATERIALS AND METHODS This study was HIPAA-compliant and approved by the institutional review board. Preoperative 1.5-T multiparametric endorectal MR images of 119 PC patients (dataset A, 71 patients; dataset B, 48 patients) were analyzed, and 265 PC and normal peripheral zone regions of interests (ROIs) were identified through histologic and MR consensus review. The 10th percentile average apparent diffusion coefficient (ADC) value, average ADC value, and skewness of T2-weighted signal-intensity histogram were evaluated with area under the receiver operating characteristic curve (AUC). The image features were combined with a linear discriminant analysis classifier and evaluated both on the image dataset of each type of imager alone (leave-one-patient-out evaluation) and across the datasets (training on one dataset, testing on the other). Spearman correlation coefficient was calculated between the image features and ROI-specific Gleason scores. RESULTS AUC values of the image features combined were 0.95 ± 0.02 (standard error) and 0.88 ± 0.03 on dataset B and dataset A alone, respectively, and 0.96 ± 0.02 and 0.89 ± 0.03 when training on dataset A and testing on dataset B and vice versa, respectively. Spearman correlation coefficients between Gleason scores and the ADC features were between -0.27 and -0.34. CONCLUSION Consistently across images from datasets A and B, the 10th percentile ADC value, average ADC value, and T2-weighted skewness can distinguish PC from normal-tissue ROIs, and ADC features correlate moderately with ROI-specific Gleason scores.

Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations

PURPOSE Somatic mutations and copy number variation in the ERBB family are frequent in urothelial carcinoma (UC) and may represent viable therapeutic targets. We studied whether afatinib (an oral, irreversible inhibitor of the ErbB family) has activity in UC and if specific ERBB molecular alterations are associated with clinical response. PATIENTS AND METHODS In this phase II trial, patients with metastatic platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance. The primary end point was 3-month progression-free survival (PFS3). Prespecified tumor analysis for alterations in EGFR, HER2, ERBB3, and ERBB4 was conducted. RESULTS The first-stage enrollment goal of 23 patients was met. Patient demographic data included: 78% male, median age 67 years (range, 36 to 82 years), hemoglobin < 10 g/dL in 17%, liver metastases in 30%, median time from prior chemotherapy of 3.6 months, and Eastern Cooperative Oncology Group performance status ≤ 1 in 100%. No unexpected toxicities were observed; two patients required dose reduction for grade 3 fatigue and rash. Overall, five of 23 patients (21.7%) met PFS3 (two partial response, three stable disease). Notably, among the 21 tumors analyzed, five of six patients (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 6.3, and 5.0 months, respectively) versus none of 15 patients without alterations (P < .001). Three of four patients with HER2 amplification and three of three patients with ERBB3 somatic mutations (G284R, V104M, and R103G) met PFS3. One patient with both HER2 amplification and ERBB3 mutation never progressed on therapy, but treatment was discontinued after 10.3 months as a result of depressed ejection fraction. The median time to progression/discontinuation was 6.6 months in patients with HER2/ERBB3 alterations versus 1.4 months in patients without alterations (P < .001). CONCLUSION Afatinib demonstrated significant activity in patients with platinum-refractory UC with HER2 or ERBB3 alterations. The potential contribution of ERBB3 to afatinib sensitivity is novel. Afatinib deserves further investigation in molecularly selected UC.

Dynamic Contrast-enhanced MR Imaging Curve-type Analysis: Is It Helpful in the Differentiation of Prostate Cancer from Healthy Peripheral Zone?

PURPOSE To evaluate the performance and interobserver agreement of qualitative dynamic contrast material enhanced magnetic resonance (MR) imaging curve analysis as described in the Prostate Imaging Reporting and Data System (PI-RADS) for the differentiation of prostate cancer (PCa) from healthy prostatic tissue in the peripheral zone (PZ). MATERIALS AND METHODS This Health Insurance Portability and Accountability Act-compliant institutional review board-approved retrospective analysis included 120 consecutive pretreatment dynamic contrast-enhanced (DCE) MR imaging PCa examinations. Regions of interest (ROIs) were placed in 251 spots, including 95 (37.8%) in healthy PZ tissue and 156 (62.2%) in PCa, by using detailed histologic-multiparametric MR correlation review. Three radiologists reviewed the DCE time curves and assessed qualitative curve types as described in PI-RADS: type 1 (progressive), type 2 (plateau), or type 3 (washout). Receiver operating characteristic curve analysis was used to assess accuracy in differentiating PCa from healthy tissue on the basis of curve type, and κ was calculated to assess interobserver agreement. RESULTS Receiver operating characteristic curves were similar for all observers, but mean areas under the receiver operating characteristic curve were poor (0.58 ± 0.04 [standard deviation] to 0.63 ± 0.04). No differences in accuracy were seen for varying DCE time resolution and imaging length. Observer agreement in assessment of type 3 versus types 1 or 2 curves was substantial (0.66 < κ < 0.79), better for PCa ROIs than for healthy-tissue ROIs. The agreement between type 1 and type 2 curves was moderate to substantial (0.49 < κ < 0.78). CONCLUSION Qualitative DCE MR imaging time-curve-type analysis performs poorly for differentiation of PCa from healthy prostatic tissue. Interobserver agreement is excellent in assessment of type 3 curves but only moderate for type 1 and 2 curves.

Deregulation of a Hox Protein Regulatory Network Spanning Prostate Cancer Initiation and Progression

Purpose: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare. Experimental Design: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein–protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets. Results: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors. Conclusion: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression. Clin Cancer Res; 18(16); 4291–302. ©2012 AACR.

Whole-Exome Sequencing of Muscle-Invasive Bladder Cancer Identifies Recurrent Mutations of UNC5C and Prognostic Importance of DNA Repair Gene Mutations on Survival

Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. Experimental Design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22–0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. Clin Cancer Res; 20(24); 6605–17. ©2014 AACR.