Whole-mount Sections Research Articles

Magnetic Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds to Correlate Images with Whole Mount Pathology

We evaluated the accuracy of magnetic resonance imaging in determining the size and shape of localized prostate cancer. The subjects were 114 men who underwent multiparametric magnetic resonance imaging before radical prostatectomy with patientspecific mold processing of the specimen from 2013 to 2015. T2-weighted images were used to contour the prostate capsule and cancer suspicious regions of interest. The contours were used to design and print 3-dimensional custom molds, which permitted alignment of excised prostates with magnetic resonance imaging scans. Tumors were reconstructed in 3 dimensions from digitized wholemount sections. Tumors were then matched with regions of interest and the relative geometries were compared. Of the 222 tumors evident on whole mount sections 118 had been identified on magnetic resonance imaging. For the 118 regions of interest mean volume was 0.8 cc and the longest 3-dimensional diameter was 17 mm. However, for matched pathological tumors, of which most were Gleason score 3 + 4 or greater, mean volume was 2.5 cc and the longest 3-dimensional diameter was 28mm. The median tumor had a 13.5 mm maximal extent beyond the magnetic resonance imaging contour and 80% of cancer volume from matched tumors wasoutside region of interest boundaries. Size estimation was most accurate in the axial plane and least accurate along the base-apex axis. Magnetic resonance imaging consistently underestimates the size and extent of prostate tumors. Prostate cancer foci had an average diameter 11mm longer and a volume 3 times greater than T2-weighted magnetic resonance imaging segmentations. These results may have important implications for the assessment andtreatment of prostate cancer.

Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma.

We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC.

Endosphenoidal coil for intraoperative magnetic resonance imaging of the pituitary gland during transsphenoidal surgery.

OBJECTIVE Pituitary MR imaging fails to detect over 50% of microadenomas in Cushing's disease and nearly 80% of cases of dural microinvasion. Surface coils can generate exceptionally high-resolution images of the immediately adjacent tissues. To improve imaging of the pituitary gland, a receive-only surface coil that can be placed within the sphenoid sinus (the endosphenoidal coil [ESC]) during transsphenoidal surgery (TSS) was developed and assessed. METHODS Five cadaver heads were used for preclinical testing of the ESC. The ESC (a double-turn, 12-mm-diameter surface coil made from 1-mm-diameter copper wire) was developed to obtain images in a 1.5-T MR scanner. The ESC was placed (via a standard sublabial TSS approach) on the anterior sella face. Clinical MR scans were obtained using the 8-channel head coil and ESC as the receiver coils. Using the ESC, ultra-high-resolution, 3D, balanced fast field echo (BFFE) and T1-weighted imaging were performed at resolutions of 0.25 × 0.25 × 0.50 mm3 and 0.15 × 0.15 × 0.30 mm3, respectively. RESULTS Region-of-interest analysis indicated a 10-fold increase in the signal-to-noise ratio (SNR) of the pituitary when using the ESC compared with the 8-channel head coil. ESC-related improvements (p < 0.01) in the SNR were inversely proportional to the distance from the ESC tip to the anterior pituitary gland surface. High-resolution BFFE MR imaging obtained using ESC revealed a number of anatomical features critical to pituitary surgery that were not visible on 8-channel MR imaging, including the pituitary capsule, the intercavernous sinus, and microcalcifications in the pars intermedia. These ESC imaging findings were confirmed by the pathological correlation with whole-mount pituitary sections. CONCLUSIONS ESC can significantly improve SNR in the sellar region intraoperatively using current 1.5-T MR imaging platforms. Improvement in SNR can provide images of the sella and surrounding structures with unprecedented resolution. Clinical use of this ESC may allow for MR imaging detection of previously occult pituitary adenomas and identify microscopic invasion of the dura or cavernous sinus.

Abstract A35: Increased expression of PCGEM1 lncRNA in prostate cancer of African American men

Abstract Introduction: Prostate cancer (CaP) affects 1 in 7 men throughout their life time. One of the major risk factors for the development of CaP is race/ethnicity. African American (AA) men have significantly higher incidence and mortality from CaP compared to Caucasian American (CA). Our laboratory and others have recently described that cancer driver genes, including ERG and PTEN, have significantly different frequencies in AA versus CA CaP. In recent years progress has been made in evaluating the expression and role of long noncoding RNAs (lncRNAs) in prostate tumorigenesis, but variations in lncRNAs expression across race/ethnicity (AA vs CA) remains poorly understood. The objective of this study is to compare the expression of CaP related lncRNAs among AA and CA men. Methods: Whole-mounted prostate sections from 30 patients, 15 AA and 15 CA matched for age, Gleason score and pathologic stage, were evaluated for the expression of lncRNAs that have been reported to be associated with CaP or other cancers. Probe sets were designed for the following 20 lncRNAs: CTBP1-AS, PCA3, PRNCR1, Hoxa11as, H19, HOTTIP, MEG3, PCGEM1, ST7OT1, SChLAP1, ANRIL/p15AS/CDK2BAS, HOTAIR, SRA-1/SRA, MALAT1/NEAT2, GAS5/SNHG2, PlncRNA-1/CBR3-AS1, Xist, hY1/RNY1, hY3/RNY3, PCAT-1. Tumor and benign epithelium was dissected under microscope from the slides, and the isolated RNA, passing BioAnalyzer quality control, was evaluated by using Nanostring platform. PCGEM1 expression analysis was updated in an existing QRT-PCR dataset of 88 patients (24 AA and 64 CA). Results: Copy numbers of each gene, normalized to ten housekeeping genes, was compared between tumor and matched normal prostate epithelium and across ethnic groups. We have identified a panel of lncRNAs (CTBP1-AS, PCA3, PCAT-1, PRNCR1) overexpressed in tumor versus matched normal samples in 95% of patients when combined. Three genes were significantly downregulated in CaP (MEG3, HOTTIP, H19). Most significantly, PCGEM1 had robust overexpression in prostate tumors (over 10-fold upregulation) only in AA patients (7 of 15) but not in CAs (0 of 15), which was in concordance with evaluation of PCGEM1 in existing dataset, underscoring selective overexpression in AA CaP. Conclusions: PCGEM1 was robustly overexpressed only in AA patients, whereas several lncRNAs were overexpressed (CTBP1-AS, PCA3, PCAT-1, PRNCR1) or downregulated (MEG3, HOTTIP, H19) in tumors of both AA and CA patients. Biomarker potential and biological functions of PCGEM1 are under further investigation. Citation Format: Jocelyn Lee, Muhammad Jamal, Wusheng Yan, Denise young, Yingjie Song, Yongmei Chen, Shilpa Katta, Lakshmi Ravindranath, Alagarsamy Srinivasan, Jennifer Cullen, Jacob Kagan, Sudhir Srivastava, Albert Dobi, Inger L. Rosner, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava, Gyorgy Petrovics. Increased expression of PCGEM1 lncRNA in prostate cancer of African American men. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A35.

Whole-mount pathology of breast lumpectomy specimens improves detection of tumour margins and focality.

Technical limitations in conventional pathological evaluation of breast lumpectomy specimens may reduce diagnostic accuracy in the assessment of margin and focality. A novel technique based on whole-mount serial sections enhances sampling while preserving specimen conformation and orientation. The aim of this study was to investigate assessment of focality and margin status by the use of whole-mount serial sections versus simulated conventional sections in lumpectomies. Two pathologists interpreted whole-mount serial sections and simulated conventional sections for 58 lumpectomy specimens by reporting the closest margin and focality. Measurements were compared by the use of McNemar's chi-squared test. Statistically significant differences were observed in the assignment of both margin positivity (P = 0.014) and multifocality (P = 0.021). A positive margin or multifocal disease was identified by the use of whole-mount serial sections but missed in the simulated conventional assessment in 10.3% and 17.2% of all cases, respectively. There was no case in which a positive margin was detected only in the simulated conventional assessment. The whole-mount technique is more sensitive than conventional assessment for identifying a positive margin or multifocal disease in breast lumpectomy specimens. Undersampling in conventional sections was implicated in almost all cases of discordance. The majority of positive margins or secondary foci identified only in whole-mount serial sections concerned in-situ disease.

Update on histopathological evaluation of lymphadenectomy specimens from prostate cancer patients.

Metastases to lymph nodes (LNs) represent an unfavorable prognostic factor in patients with prostate cancer (PCa). Histological examination represents the gold standard in the evaluation of the lymphadenectomy (LND) specimens for the presence of secondary deposits. The metastatic detection rate can vary according to the approach adopted in the microscopic analysis of the LNs, which includes frozen-section examination, total inclusion of the tissue with and without whole-mount sections, serial sectioning, and the application of immunohistochemistry. The assessment of the sentinel LN, the search for micrometastases, and the evaluation of atypical LN metastatic sites further contribute to the detection of the metastatic spread. In this review, an update on the histopathological evaluation of LND specimens in patients with PCa is given, and focus is made on their clinical and prognostic significance.

Stability of limbal stem cell deficiency after mechanical and thermal injuries in mice

We studied the reproducibility and stability of limbal stem cell deficiency (LSCD) in mice following controlled injuries to the corneal and limbal epithelia. In one method, corneal and limbal epithelia were entirely removed with a 0.5 mm metal burr. In the other, limbus to limbus epithelial removal with the burr was followed by thermal injury to the limbus. These two methods were compared with a previously published one. Unwounded corneas were used as control. The corneas were examined monthly for three months by slit lamp with fluorescein staining. Immunofluorescence staining for cytokeratin 12 and 8 on corneal wholemount and cross sections were performed to determine the phenotype of the epithelium. Mechanical shaving of the epithelium, with or without thermal injury, resulted in a reproducible state of LSCD marked by superficial neovascularization, reduce of keratin 12 expression and presence of goblet cells on the cornea. The phenotype was stable in 100% of the eyes up to at least three months. Thermal injury produced a more severe phenotype with more significant stromal opacification. These corneal injury models may be useful for studying the mechanisms leading to limbal stem cell deficiency.

A fully automatic computer aided diagnosis system for peripheral zone prostate cancer detection using multi-parametric magnetic resonance imaging

Multiparametric (mp)-Magnetic Resonance Imaging (MRI) is emerging as a powerful test to diagnose and stage prostate cancer (PCa). However, its interpretation is a time consuming and complex feat requiring dedicated radiologists. Computer-aided diagnosis (CAD) tools could allow better integration of data deriving from the different MRI sequences in order to obtain accurate, reproducible, non-operator dependent information useful to identify and stage PCa. In this paper, we present a fully automatic CAD system conceived as a 2-stage process. First, a malignancy probability map for all voxels within the prostate is created. Then, a candidate segmentation step is performed to highlight suspected areas, thus evaluating both the sensitivity and the number of false positive (FP) regions detected by the system. Training and testing of the CAD scheme is performed using whole-mount histological sections as the reference standard. On a cohort of 56 patients (i.e. 65 lesions) the area under the ROC curve obtained during the voxel-wise step was 0.91, while, in the second step, a per-patient sensitivity of 97% was reached, with a median number of FP equal to 3 in the whole prostate. The system here proposed could be potentially used as first or second reader to manage patients suspected to have PCa, thus reducing both the radiologist's reporting time and the inter-reader variability. As an innovative setup, it could also be used to help the radiologist in setting the MRI-guided biopsy target.

Detection of prostate cancer index lesions with multiparametric magnetic resonance imaging (mp-MRI) using whole-mount histological sections as the reference standard.

To evaluate the sensitivity of multiparametric magnetic resonance imaging (mp-MRI) for detecting prostate cancer foci, including the largest (index) lesions. In all, 115 patients with biopsy confirmed prostate cancer underwent mp-MRI before radical prostatectomy. A single expert radiologist recorded all prostate cancer foci including the index lesion 'blinded' to the pathologist's biopsy report. Stained whole-mount histological sections were used as the reference standard. All lesions were contoured by an experienced uropathologist who assessed their volume and pathological Gleason score. All lesions with a volume of >0.5mL and/or pathological Gleason score of >6 were defined as clinically significant prostate cancer. Multivariate analysis was used to ascertain the characteristics of lesions identified by MRI. In all, 104 of 115 index lesions were correctly diagnosed by mp-MRI (sensitivity 90.4%; 95% confidence interval [CI] 83.5-95.1%), including 98/105 clinically significant index lesions (93.3%; 95% CI 86.8-97.3%), among which three of three lesions had a volume of <0.5mL and Gleason score of >6. Overall, mp-MRI detected 131/206 lesions including 13 of 68 'insignificant' prostate cancers. The multivariate logistic regression modelling showed that pathological Gleason score (odds ratio [OR] 11.7, 95% CI 2.3-59.8; P = 0.003) and lesion volume (OR 4.24, 95% CI 1.3-14.7; P = 0.022) were independently associated with the detection of index lesions at MRI. This study shows that mp-MRI has a high sensitivity for detecting clinically significant prostate cancer index lesions, while having disappointing results for the detection of small-volume, low Gleason score prostate cancer foci. Thus, mp-MRI could be used to stratify patients according to risk, allowing better treatment selection.

The correlation between the electrode configuration and histopathology of irreversible electroporation ablations in prostate cancer patients.

Purpose Irreversible electroporation (IRE) is a novel minimally invasive therapy for prostate cancer using short electric pulses to ablate prostate tissue. The purpose of this study is to determine the IRE effects in prostate tissue and correlate electrode configuration with the histology of radical prostatectomy (RP) specimens. We hypothesize that the area within the electrode configuration is completely ablated and that the area within the electrode configuration is predictive for the ablated area after treatment.MethodsA prospective phase I/II study was conducted in 16 consecutive patients with histopathologically confirmed prostate cancer scheduled for RP. Focal or extended IRE treatment of the prostate was performed 4 weeks prior to RP. The locations of the electrodes were used to calculate the planned ablation zone. Following RP, the specimens were processed into whole-mount sections, histopathology (PA) was assessed and ablation zones were delineated. The area of the tissue alteration was determined by measuring the surface. The planned and the histological ablation zones were compared, analysed per individual patient and per protocol (focal vs. extended).ResultsAll cells within the electrode configuration were completely ablated and consisted only of necrotic and fibrotic tissue without leaving any viable cells. The histological ablation zone was always larger than the electrodes configuration (2.9 times larger for the 3 electrodes configuration and 2.5 times larger for the ≥4 electrode configuration). These ablation effects extended beyond the prostatic capsule in the neurovascular bundle in 13 out of 15 cases.ConclusionsIRE in prostate cancer results in completely ablated, sharply demarcated lesions with a histological ablation zone beyond the electrode configuration. No skip lesions were observed within the electrode configuration.Clinical trialsClinicalTrials.gov Identifier: NCT01790451 https://clinicaltrials.gov/ct2/show/NCT01790451

Abstract 5268: Differences in ERG and ANXA2 expression between Caucasian Americans and African Americans highlight distinct pathologic features of prostate cancer progression

Abstract Introduction: Annexin A2 (ANXA2) is a Ca2+-dependent phospholipid binding protein with multiple cellular functions that include the maintenance of epithelial cell polarity. It is expressed in the luminal and basal prostate epithelium. In PIN and in moderately differentiated tumors, it is either absent or expressed focally. In contrast, a high level of ANXA2 is detected in poorly differentiated high-grade tumors. TMPRSS2:ERG gene fusion that occurs in a majority of prostate cancers results in the overexpression of ERG. We have previously reported a reciprocal correlation between ERG and ANXA2 expression in tumor specimens from a cohort 40 Caucasian American (CA) patients and showed that this is regulated through transcriptional repression of ANXA2 by ERG. This study compares the correlation of ERG and ANXA2 status in CA and African Americans (AA) to prostate cancer progression. Methods: ERG and ANXA2 expression were evaluated on whole-mounted prostate sections from 40 CA and 40 AA patients and on tissue microarrays (TMA) derived from the radical prostatectomies (RP) of 99 patients (59 CA and 40 AA) by immunochemistry. Both cohorts were matched for post RP follow-up and pathologic stage. Patients were defined as ERG- or ANXA2+ when all of the TMA cores of a given subject were ERG- or ANXA2+. Conversely, patients were defined as ERG+ or ANXA2- when any of the cores were ERG+ or ANXA-. The ERG and ANXA2 status of tumors were correlated to Gleason score and prostate cancer recurrence. Recurrence was defined as 0.2 ng/ml of serum PSA, eight weeks after RP followed by a second PSA measurement of ≥0.2 ng/ml, the initiation of radiation or hormonal therapy, or metastasis. Results: In whole mount sections, a reciprocal correlation of ERG and ANXA2 expression was noted in a majority (80%) of the CAs. However, this was observed only in 55% of AA cases. ERG+ tumors were detected in 65% of CAs as compared to 25% of AAs. In the TMAs, tumor cores from CAs are more likely to be ERG+ (46%) than those from AAs (30%). When scored by patients, CA cases were twice as likely to be ERG+/ANXA2- than ERG-/ANXA2-, while AA cases were half as likely to be ERG+/ANXA2- than ERG-/ANXA2- (p = 0.02). Intriguingly, ERG+/ANXA2- status in AAs was associated with higher pathologic stage (p = 0.03) and higher recurrence rate (p = 0.04). Conclusion: A higher frequency of ERG+/ANXA2- tumors was observed in CA men, while ERG-/ANXA2- tumors were more frequent among AA men. Surprisingly, ERG+/ANXA2- status in AAs is associated with poorer pathologic stage and prostate cancer recurrence. Taken together, our results suggest potential utility of ERG+/ANXA2- status for early identification of prostate cancer progression in AA men. Citation Format: Shyh-Han Tan, Denise Young, Yongmei Chen, Albert Dobi, Jennifer Cullen, Gyorgy Petrovics, Isabell A. Sesterhenn, Shiv Srivastava. Differences in ERG and ANXA2 expression between Caucasian Americans and African Americans highlight distinct pathologic features of prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5268. doi:10.1158/1538-7445.AM2015-5268

Evaluation of the 'Prostate Interdisciplinary Communication and Mapping Algorithm for Biopsy and Pathology' (PIC-MABP).

Experience from interdisciplinary cooperation revealed the need for a prostate mapping scheme to communicate multiparametric MRI (mpMRI) findings between radiologists, urologists, and pathologists, which should be detailed, yet easy to memorize. For this purpose, the 'Prostate interdisciplinary communication and mapping algorithm for biopsy and pathology' (PIC-MABP) was developed. This study evaluated the accuracy of the PIC-MABP system. PIC-MABP was tested and validated in findings of 10 randomly selected patients from routine clinical practise with 18 histologically proven cancer lesions. Patients received an mpMRI of the prostate prior to prostatectomy. After surgery the prostates were prepared as whole-mount step sections. Cancer lesions, which were found suspicious on mpMRI, were assigned to the according PIC-MABP sectors by a radiologist. MpMRI slides were masked and sent to seven urologists from different centres, providing only the PIC-MABP location of each lesion. Urologists marked the accordant regions. Then mpMRI slides were unmasked, and the correctness of each mark was evaluated. One hundred and seventeen of the 126 marks (93%) were correctly assigned. Detection rates differed for lesions >0.5 cc compared with lesions <0.5 cc (p < 0.005): 3/7 (43%) marks were correctly assigned in lesions <0.3 cc, 16/21 (76%) in lesions with 0.3-0.5 cc, and 98/98 (100%) in lesions >0.5 cc. Interobserver agreement was good for lesions >0.5 cc and poor for lesions <0.3 cc (Fleiss Kappa 1 vs. 0.0175). PIC-MABP seems to be a reliable system to communicate the location of mpMRI findings >0.5 cc between different disciplines and can be a useful guidance for cognitive mpMRI/TRUS fusion biopsy.

Flattened Tumor Requires a More Careful Attention for Residual Distal Cancer Spread in Locally Advanced Lower Rectal Carcinoma after Chemoradiotherapy

Background/Aims: Limited data are available on distal resection margin (DRM) for lower rectal cancer (LRC) after preoperative chemoradiotherapy (pre-CRT); thus, we aimed to establish the criteria for DRMs as estimated by the macroscopic tumor appearance. Methods: This was a pathological study using whole-mount sections that included the entire circumference of tumor. Residual cancer spread located most distally from the macroscopic tumor border was mainly evaluated. Results: A retrospective cohort of 42 consecutive patients with locally advanced LRC after pre-CRT was enrolled, and 38 patients were eligible for this study. According to the macroscopic tumor appearance, 18 patients had raised-type and 20 had flattened-type tumors. Patients with flattened-type tumors were closely associated with histopathological regression grade. Residual distal cancer spread (RDCS) was located ≤4.0 mm (median, 0.1 mm) in the raised-type tumors and ≤17.1 mm (median, 4.2 mm) in the flattened-type tumors. RDCS in flattened-type tumors was distributed diffusely and distally from the tumor border (p = 0.022). Conclusion: Even in patients evaluated as pre-CRT responders, flattened tumors often accompanied distally located residual cancer that had spread from the tumor border and require more careful attention in order to ensure cancer clearance.

Rotating frame relaxation imaging of prostate cancer: Repeatability, cancer detection, and Gleason score prediction.

To investigate relaxation along a fictitious field (RAFF) and continuous wave (cw) T1ρ imaging of prostate cancer (PCa) in the terms of repeatability, PCa detection, and characterization. Thirty-six patients (PSA 11.6 ± 7.6 ng/mL, mean ± standard deviation) with histologically confirmed PCa underwent two repeated 3T MR examinations using surface array coils before prostatectomy. Relaxation along fictitious field, cw T1ρ, and T2 relaxation times (TRAFF, T1ρcw, T2) were measured and averaged over regions of interest placed in PCa, normal peripheral zone (PZ), and normal central gland (CG) positioned using whole-mount prostatectomy sections and anatomical T2-weighted images. Receiver operating characteristic curve analysis with area under the curve (AUC) was calculated to distinguish PCa from PZ/CG and PCa with Gleason score (GS) of 3+3 from GS of 3+4/≥ 3+4. TRAFF and T1ρcw relaxation times were repeatable with coefficients of repeatability as a percentage of median value in the range of 7.8-23.2%. AUC (mean, 95% confidence interval) in the differentiation of PCa with GS of 3+3 from PCa with CS of ≥ 3+4 were 0.88 (0.72-0.99), 0.69 (0.46-0.90), and 0.68 (0.45-0.88), for TRAFF, T1ρcw, and T2, respectively. In quantitative region of interest based analysis, TRAFF outperformed T1ρcw and T2 in PCa detection and characterization.

Sialolipoma of Minor Salivary Gland in Uvula

Lipomatous lesions of the salivary glands are rare, accounting for less than 0.5% of all parotid gland tumours. Distinct microscopic variants of lipoma of the salivary glands, e.g. angiolipoma, fibrolipoma, pleomorphic lipoma and spindle-cell lipoma have been reported. A 45 year-old male patient with mass on uvula was presented. The specimen was capsulated, yellow coloured, soft tissue with 1.3 cm in greatest diameter. Whole-mount section showed tumor composed by mature adipocytes, salivary gland parenchymal tissue and lymphoid follicles surrounded by a fibrous capsule. Salivary gland component consist acinar and ductal elements. In some areas, glandular components were atrophic. Lymphoid follicles and focal fibrosis were seen. Oncocytic, sebaceous, and squamous metaplasia were not observed. Sialolipomas were composed predominantly of adipose tissue and showed expansive growth with fibrous capsule. Sialolipomas were reported at parotid gland, submandibular gland, hard and soft palate. To our knowledge, such a case in uvula localization was not previously presented.

Quantitative Ultrasound Spectroscopic Imaging for Characterization of Disease Extent in Prostate Cancer Patients

Three-dimensional quantitative ultrasound spectroscopic imaging of prostate was investigated clinically for the noninvasive detection and extent characterization of disease in cancer patients and compared to whole-mount, whole-gland histopathology of radical prostatectomy specimens. Fifteen patients with prostate cancer underwent a volumetric transrectal ultrasound scan before radical prostatectomy. Conventional-frequency (~5MHz) ultrasound images and radiofrequency data were collected from patients. Normalized power spectra were used as the basis of quantitative ultrasound spectroscopy. Specifically, color-coded parametric maps of 0-MHz intercept, midband fit, and spectral slope were computed and used to characterize prostate tissue in ultrasound images. Areas of cancer were identified in whole-mount histopathology specimens, and disease extent was correlated to that estimated from quantitative ultrasound parametric images. Midband fit and 0-MHz intercept parameters were found to be best associated with the presence of disease as located on histopathology whole-mount sections. Obtained results indicated a correlation between disease extent estimated noninvasively based on midband fit parametric images and that identified histopathologically on prostatectomy specimens, with an r2 value of 0.71 (P<.0001). The 0-MHz intercept parameter demonstrated a lower level of correlation with histopathology. Spectral slope parametric maps offered no discrimination of disease. Multiple regression analysis produced a hybrid disease characterization model (r2=0.764, P<.05), implying that the midband fit biomarker had the greatest correlation with the histopathologic extent of disease. This work demonstrates that quantitative ultrasound spectroscopic imaging can be used for detecting prostate cancer and characterizing disease extent noninvasively, with corresponding gross three-dimensional histopathologic correlation.

Non-invasive estimation of prostate cancer aggressiveness using diffusion-weighted MRI and 3D proton MR spectroscopy at 3.0 T

Clinical management of prostate cancer increasingly aims to distinguish aggressive types that require immediate and radical treatment from indolent tumors that are candidates for watchful waiting. This requires reliable and reproducible parameters to effectively control potential cancer progression. Magnetic resonance imaging (MRI) may provide a non-invasive means for this purpose. To assess the value of diffusion-weighted imaging and proton MR spectroscopy for the prediction of prostate cancer (PCa) aggressiveness. In 39 of 64 consecutive patients who underwent endorectal 3-T MRI prior to radical prostatectomy, prostate specimens were analyzed as whole-mount step sections. Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor/healthy tissue), choline/citrate (CC), and (choline + creatine)/citrate (CCC) ratios were correlated with Gleason scores (GS) from histopathological results. The power to discriminate low (GS ≤ 6) from higher-risk (GS ≥ 7) tumors was assessed with receiver operating characteristics (area under the curve [AUC]). Resulting threshold values were used by a blinded reader to distinguish between aggressive and indolent tumors. Ninety lesions (1 × GS = 5, 41 × GS = 6, 36 × GS = 7, 12 × GS = 8) were considered. nADC (AUC = 0.90) showed a higher discriminatory power than ADC (AUC = 0.79). AUC for CC and CCC were 0.73 and 0.82, respectively. Using either nADC < 0.46 or CCC > 1.3, as well as both criteria for aggressive PCa, the reader correctly identified aggressive and indolent tumors in 31 (79%), 28 (72%), and 33 of 39 patients (85%), respectively. Predictions of tumor aggressiveness from TRUS-guided biopsies were correct in 27 of 36 patients (75%). The combination of a highly sensitive normalized ADC with a highly specific CCC was found to be well suited to prospectively estimate PCa aggressiveness with a similar diagnostic accuracy as biopsy results.

Detection of the index tumour and tumour volume in prostate cancer using T2‐weighted and diffusion‐weighted magnetic resonance imaging (MRI) alone

To examine the performance of T2-weighted (T2W) and diffusion-weighted (DW) magnetic resonance imaging (MRI) for detecting the index tumour in patients with prostate cancer and to examine the agreement between MRI and histology when assessing tumour volume (TV) and overall tumour burden. The study included 199 consecutive patients with biopsy confirmed prostate cancer randomised to MRI before radical prostatectomy from December 2009 to July 2012. MRI-detected tumours (MRTs) were ranked from 1 to 3 according to decreasing volume and were compared with histologically detected tumours (HTs) ranked from 1 to 3, with HT 1 = index tumour. Whole-mount section histology was used as a reference standard. The TVs of true-positive MRTs (MRTVs 1-3) were compared with the TVs found by histology (HTVs 1-3). All tumours were registered on a 30-sector map and by classifying each sector as positive/negative, the rate of true-positive and -negative sectors was calculated. The detection rate for the HT 1 (index tumour) was 92%; HT 2, 45%; and HT 3, 37%. The MRTV 1-3 vs the HTV 1-3 were 2.8 mL vs 4.0 mL (index tumour, P < 0.001), 1.0 mL vs 0.9 mL (tumour 2, P = 0.413), and 0.6 mL vs 0.5 mL (tumour 3, P = 0.492). The rate of true-positive and -negative sectors was 50% and 88%, κ = 0.39. A combination of T2W and DW MRI detects the index tumour in 92% of cases, although MRI underestimates both TV and tumour burden compared with histology.

How accurate is multiparametric MR imaging in evaluation of prostate cancer volume?

To assess the factors influencing multiparametric (MP) magnetic resonance (MR) imaging accuracy in estimating prostate cancer histologic volume (Vh). A prospective database of 202 patients who underwent MP MR imaging before radical prostatectomy was retrospectively used. Institutional review board approval and informed consent were obtained. Two independent radiologists delineated areas suspicious for cancer on images (T2-weighted, diffusion-weighted, dynamic contrast material-enhanced [DCE] pulse sequences) and scored their degree of suspicion of malignancy by using a five-level Likert score. One pathologist delineated cancers on whole-mount prostatectomy sections and calculated their volume by using digitized planimetry. Volumes of MR true-positive lesions were measured on T2-weighted images (VT2), on ADC maps (VADC), and on DCE images [VDCE]). VT2, VADC, VDCE and the greatest volume determined on images from any of the individual MR pulse sequences (Vmax) were compared with Vh (Bland-Altman analysis). Factors influencing MP MR imaging accuracy, or A, calculated as A = Vmax/Vh, were evaluated using generalized linear mixed models. For both readers, Vh was significantly underestimated with VT2 (P < .0001, both), VADC (P < .0001, both), and VDCE (P = .02 and P = .003, readers 1 and 2, respectively), but not with Vmax (P = .13 and P = .21, readers 1 and 2, respectively). Mean, 25th percentile, and 75th percentile, respectively, for Vmax accuracy were 0.92, 0.54, and 1.85 for reader 1 and 0.95, 0.57, and 1.77 for reader 2. At generalized linear mixed (multivariate) analysis, tumor Likert score (P < .0001), Gleason score (P = .009), and Vh (P < .0001) significantly influenced Vmax accuracy (both readers). This accuracy was good in tumors with a Gleason score of 7 or higher or a Likert score of 5, with a tendency toward underestimation of Vh; accuracy was poor in small (<0.5 cc) or low-grade (Gleason score ≤6) tumors, with a tendency toward overestimation of Vh. Vh can be estimated by using Vmax in aggressive tumors or in tumors with high Likert scores.

Abstract C18: ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine

Abstract Introduction: Prostate cancer incidence and associated mortality is highest in African American men in comparison to other ethnicities. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different biochemical pathways of prostate carcinogenesis between African American and Caucasian men. Emerging observations of the ethnic differences of the ERG oncogenic activation, the most common prostate cancer genomic alteration described in Western countries, provides new insights into the ERG based stratification of prostate cancers in the context of the increasingly diverse ethnic patient populations in The United States. This rapidly advancing knowledge has potential to stratify prostate cancers by ERG typing in a given patient population that may eventually lead to new targeted treatments. Experimental procedures: For the comparative evaluation of ERG frequencies, ERG oncoprotein expression was analyzed in whole-mounted sections of 91 Caucasian American and 91 African American prostate cancer cases matched for age, Gleason score and pathologic stage. To evaluate the association of high grade tumors with ERG status prostate cancer specimens with a primary Gleason pattern of 4 or 5 or cumulative Gleason score of 8-10 from a total of 63 African American patients and 63 Caucasian American patients matched for age. For the comprehensive evaluation of ERG frequencies in African American patients we have examined 306 whole mounted prostate specimens representing hormone naïve cases with a minimum of two years of follow up after radical prostatectomy. ERG oncoprotein was evaluated by immunohistochemistry in all cases and the genomic rearrangement of the ERG gene was assessed in selected cases by FISH assy. Results: Markedly greater frequencies of ERG oncoprotein expression was noted in the index tumors of the Caucasian Americans (63.3%) compared to the African Americans (28.6%). The observed difference was even more pronounced in higher grade disease indicating significantly lower ERG frequencies among African American (16%) patients in comparison to Caucasian American men (49%). Comprehensive evaluation of ERG frequencies revealed that ERG positive tumors were more likely to be present in index tumors of younger African American men, whereas, ERG negative tumors were significantly associated with higher pathologic T stage when all tumors were assessed. Conclusions: ERG-based stratification defines molecular subtypes of prostate cancers. Association of ERG negative status with high grade tumors and poor prognostic features in African American patients warrants the development of informative marker panels that includes ERG to aid in diagnostic, prognostic and targeted therapy settings. The results of the present study underscore that typing prostate cancers for ERG significantly contributes to the understanding of causal alterations resulting in higher incidence and associated mortality among African American prostate cancer patients. Citation Format: Albert Dobi, Philip Rosen, James Farrell, Michael Degon, Denise Young, Sudhir Srivastava, Jacob Kagan, Gyorgy Petrovics, Jennifer Cullen, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava. ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C18. doi:10.1158/1538-7755.DISP13-C18