Faculty Bibliography

PURPOSE: Human endogenous retroviruses (HERV) encode 8% of the human genome. While HERVs may play a role in autoimmune and neoplastic disease, no mechanistic association has yet been established. We studied the expression and immunogenicity of a HERV-K GAG protein encoded on chromosome 22q11.23 in relation to the clinical course of prostate cancer. EXPERIMENTAL DESIGN: In vitro expression of GAG-HERV-K was analyzed in panels of normal and malignant tissues, microarrays, and cell lines, and effects of demethylation and androgen stimulation were evaluated. Patient sera were analyzed for seroreactivity to GAG-HERV-K and other self-antigens by ELISA and seromics (protein array profiling). RESULTS: GAG-HERV-K expression was most frequent in prostate tissues and regulated both by demethylation of the promoter region and by androgen stimulation. Serum screening revealed that antibodies to GAG-HERV-K are found in a subset of patients with prostate cancer (33 of 483, 6.8%) but rarely in male healthy donors (1 of 55, 1.8%). Autoantibodies to GAG-HERV-K occurred more frequently in patients with advanced prostate cancer (29 of 191 in stage III-IV, 21.0%) than in early prostate cancer (4 of 292 in stages I-II, 1.4%). Presence of GAG-HERV-K serum antibody was correlated with worse survival of patients with prostate cancer, with a trend for faster biochemical recurrence in patients with antibodies to GAG-HERV-K. CONCLUSIONS: Preferential expression of GAG-HERV-K ch22q11.23 in prostate cancer tissue and increased frequency of autoantibodies observed in patients with advanced prostate cancer make this protein one of the first bona fide retroviral cancer antigens in humans, with potential as a biomarker for progression and biochemical recurrence rate of prostate cancer. Clin Cancer Res; 19(22); 6112-25. (c)2013 AACR.

AIM: To assess a novel method of three-dimensional (3D) co-registration of prostate cancer digital histology and in-vivo multiparametric magnetic resonance imaging (mpMRI) image sets for clinical usefulness. MATERIAL AND METHODS: A software platform was developed to achieve 3D co-registration. This software was prospectively applied to three patients who underwent radical prostatectomy. Data comprised in-vivo mpMRI [T2-weighted, dynamic contrast-enhanced weighted images (DCE); apparent diffusion coefficient (ADC)], ex-vivo T2-weighted imaging, 3D-rebuilt pathological specimen, and digital histology. Internal landmarks from zonal anatomy served as reference points for assessing co-registration accuracy and precision. RESULTS: Applying a method of deformable transformation based on 22 internal landmarks, a 1.6 mm accuracy was reached to align T2-weighted images and the 3D-rebuilt pathological specimen, an improvement over rigid transformation of 32% (p = 0.003). The 22 zonal anatomy landmarks were more accurately mapped using deformable transformation than rigid transformation (p = 0.0008). An automatic method based on mutual information, enabled automation of the process and to include perfusion and diffusion MRI images. Evaluation of co-registration accuracy using the volume overlap index (Dice index) met clinically relevant requirements, ranging from 0.81-0.96 for sequences tested. Ex-vivo images of the specimen did not significantly improve co-registration accuracy. CONCLUSION: This preliminary analysis suggests that deformable transformation based on zonal anatomy landmarks is accurate in the co-registration of mpMRI and histology. Including diffusion and perfusion sequences in the same 3D space as histology is essential further clinical information. The ability to localize cancer in 3D space may improve targeting for image-guided biopsy, focal therapy, and disease quantification in surveillance protocols.

The presence of glandular epithelium in urinary tract biopsies poses a diagnostic challenge. Intestinal metaplasia of the urethra may be seen in many congenital, iatrogenic, and reactive conditions, as well as in association with malignant conditions such as urethral adenocarcinoma. We present a case of a 61 year-old woman presenting with microscopic hematuria. Successive biopsies showed glandular epithelium with focal atypia in close association with inflammation, but no overt malignancy. Only on surgical resection was the associated high grade adenocarcinoma revealed. When intestinal-type mucosa is present within a urinary tract biopsy, associated malignancy may be present only focally. Thorough sampling and consideration of the differential diagnosis is imperative.

IMPORTANCE: Soy consumption has been suggested to reduce risk or recurrence of prostate cancer, but this has not been tested in a randomized trial with prostate cancer as the end point. OBJECTIVE: To determine whether daily consumption of a soy protein isolate supplement for 2 years reduces the rate of biochemical recurrence of prostate cancer after radical prostatectomy or delays such recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial conducted from July 1997 to May 2010 at 7 US centers comparing daily consumption of a soy protein supplement vs placebo in 177 men at high risk of recurrence after radical prostatectomy for prostate cancer. Supplement intervention was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. INTERVENTION: Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87) or, as placebo, calcium caseinate (n=90). MAIN OUTCOMES AND MEASURES: Biochemical recurrence rate of prostate cancer (defined as development of a PSA level of >/=0.07 ng/mL) over the first 2 years following randomization and time to recurrence. RESULTS: The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3% of participants developed biochemical recurrence within 2 years of entering the trial (close to the a priori predicted recurrence rate of 30%). Among these, 22 (27.2%) occurred in the intervention group and 23 (29.5%) in the placebo group. The resulting hazard ratio for active treatment was 0.96 (95% CI, 0.53-1.72; log-rank P = .89). Adherence was greater than 90% and there were no apparent adverse events related to supplementation. CONCLUSION AND RELEVANCE: Daily consumption of a beverage powder supplement containing soy protein isolate for 2 years following radical prostatectomy did not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00765479.

BACKGROUND: A systematic literature review of magnetic resonance imaging (MRI)-targeted prostate biopsy demonstrates poor adherence to the Standards for the Reporting of Diagnostic Accuracy (STARD) recommendations for the full and transparent reporting of diagnostic studies. OBJECTIVE: To define and recommend Standards of Reporting for MRI-targeted Biopsy Studies (START). DESIGN, SETTING, AND PARTICIPANTS: Each member of a panel of 23 experts in urology, radiology, histopathology, and methodology used the RAND/UCLA appropriateness methodology to score a 258-statement premeeting questionnaire. The collated responses were presented at a face-to-face meeting, and each statement was rescored after group discussion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Measures of agreement and consensus were calculated for each statement. The most important statements, based on group median score, the degree of group consensus, and the content of the group discussion, were used to create a checklist of reporting criteria (the START checklist). RESULTS AND LIMITATIONS: The strongest recommendations were to report histologic results of standard and targeted cores separately using Gleason score and maximum cancer core length. A table comparing detection rates of clinically significant and clinically insignificant disease by targeted and standard approaches should also be used. It was recommended to report the recruitment criteria for MRI-targeted biopsy, prior biopsy status of the population, a brief description of the MRI sequences, MRI reporting method, radiologist experience, and image registration technique. There was uncertainty about which histologic criteria constitute clinically significant cancer when the prostate is sampled using MRI-targeted biopsy, and it was agreed that a new definition of clinical significance in this setting needed to be derived in future studies. CONCLUSIONS: Use of the START checklist would improve the quality of reporting in MRI-targeted biopsy studies and facilitate a comparison between standard and MRI-targeted approaches.

BACKGROUND: Androgen receptor (AR) expression in breast cancers may serve as a prognostic and predictive marker. We examined the expression pattern of AR and its phosphorylated forms, Ser-213 (AR-Ser[P]-213) and Ser-650 (AR-Ser[P]-650), in breast cancer and evaluated their association with clinicopathological parameters. METHODS: Immunohistochemistry was performed on primary and distant metastatic breast cancers and benign breast tissue using antibodies against AR, AR-Ser(P)-213, and AR-Ser(P)-650. The levels of cytoplasmic and nuclear expression were scored semiquantitatively using a histoscore. RESULTS: Nuclear staining of AR was observed in all benign breast tissue and 67% of cancer cases. Nuclear and cytoplasmic AR-Ser(P)-213 was increased in breast cancers 2-fold (P = .0014) and 1.7-fold (P = .05), respectively, compared with benign controls, whereas nuclear and cytoplasmic AR-Ser(P)-650 expression was decreased in tumors by 1.9-fold and 1.7-fold (both P < .0001), respectively. Increased expression of nuclear or cytoplasmic AR-Ser(P)-213 was observed in metastatic breast cancers (1.3-fold, P = .05), ER-negative (2.6-fold, P = .001), and invasive ductal carcinoma (6.8-fold, P = .04). AR-Ser(P)-650 expression was downregulated in lymph node-positive breast cancers (1.4-fold, P = .02) but was upregulated in invasive ductal carcinomas (3.2-fold, P < .0001) and metastases (1.5-fold, P = .003). Moreover, in ER-negative breast cancers, nuclear AR-Ser(P)-650 was decreased (1.4-fold, P = .005), and cytoplasmic AR-Ser(P)-650 was increased (1.4-fold, P = .003). CONCLUSIONS: AR and its phosphorylation at serines 213 and 650 are differentially expressed in breast cancer tumorigenesis and progression. Phosphorylation of AR at serines 213 and 650 is increased in ER-negative breast cancers, ductal carcinomas, and metastases and may have predictive value in breast cancer prognosis. Cancer 2013;000:000-000. (c) 2013 American Cancer Society.

OBJECTIVE: To study the histopathology changes and clinical features of vesical diverticula, focusing on the neoplastic entities. MATERIALS AND METHODS: We retrieved data for 108 patients with vesical diverticula from the archives of our institute during the past 15 years (1998 to 2012) and reviewed their clinical and pathologic characteristics. RESULTS: Diverticula most often involved the lateral wall, followed by the posterolateral and posterior walls of the urinary bladder. Nonneoplastic processes were found in 70 of 108 patients (65%), including inflammation, metaplasia, and urothelial hyperplasia, with or without atypia/dysplasia. Primary carcinomas arising within the diverticula were found in 36 patients (33.3%), of which 33 were urothelial carcinoma, including 5 with divergent differentiation, 2 with squamous carcinoma, and 1 with adenocarcinoma. Patient follow-up for neoplastic diverticula (mean, 59 months; range, 1-108 months) showed that no patients died of disease progression. Concurrent or subsequent urothelial carcinoma was present in the nondiverticular bladder in 19 of 36 patients (53%). Four patients with subsequent extradiverticular urothelial carcinoma showed progression, with pathology upstaging. CONCLUSION: Inflammation, metaplasia, and dysplasia are commonly seen in vesical diverticula. In our series, which includes patients who underwent endoscopic or surgical intervention and microscopic examination, those with vesical diverticula appeared to have a significantly higher risk for development of urothelial carcinoma, which can occur synchronously or precede carcinoma of the nondiverticular bladder. Compared with their non-diverticulum-associated counterparts, a significantly higher percentage of diverticulum-associated bladder carcinomas are high-grade and invasive. Conservative approaches are suggested for tumors confined within diverticula, after extensive investigation of the nondiverticular bladder.

AIM: To develop and validate a technique for construction of intermediate density tissue microarray (TMA) slides based on the transfer of tissue from pre-existing routine slides provided for pathology diagnosis with validation to show preservation of morphology and antigenicity of the transferred tissue. METHODS: A prostate cancer TMA was constructed using 20 cores from radical prostatectomy slides. This technique entails removal of the coverslip on each slide and reinforcement of the tissue by covering with Mount-Quick liquid mounting medium. The attached tissue with its new scaffold is 'biopsied' using a TMA needle (1.5 mm in diameter). The resultant biopsy disc is then transferred onto a recipient slide, with adhesion of the disc to the slide accomplished using heavy pressure. The preservation of morphology and antigenicity of this TMA is tested in comparison to a traditional TMA. RESULTS: After immunohistochemical staining, 35 of 39 cores (89.7%) on the patch TMA were intact compared with 39 of 40 cores (97.5%) on the traditional TMA (p>0.1). Expression patterns and density of the antigens (34betaE12, p63 and AMACR) on the patch TMA were almost identical to the traditional TMA. CONCLUSIONS: Patch TMA represents a viable alternative for tissue-based immunohistochemistry studies when paraffin blocks are unavailable. This may be a valuable tool for allowing the use of archival slide material for immunohistochemistry and enabling a standardised TMA platform to be used when the slides sent for review from other institutions are the only source of tissue available.

Cystic changes are common in both neoplastic and non-neoplastic kidney diseases. The most important diagnostic consideration is to rule out cystic neoplasms and hereditary polycystic kidney disease for patient management. Localized cystic disease of the kidney is a rare, nongenetic and nonprogressive cystic disease that may mimic cystic neoplasms or hereditary polycystic disease. However, reports in the literature on its pathologic characteristics are scarce, and most surgical pathologists are unfamiliar with this entity. We report the clinicopathologic characteristics of 9 such cases that mimicked renal neoplasms and were treated surgically. Nine patients, including 5 men and 4 women, had a mean age of 33.3 years (range, 18 to 56 y) at diagnosis. Two patients presented with gross hematuria. In the remaining 7 patients, localized cystic disease was discovered incidentally. None had a personal history of cystic disease of the kidney or other organs or a family history of cystic renal disease. On imaging studies, solitary multilocular cystic lesions were identified in all patients with a mean size of 2.9 cm (range, 0.8 to 6 cm). Of 7 patients with documented Bosniak classification, 4 lesions were class III, and 3 lesions were class II. Follow-up was available in 5 patients, with a mean follow-up time of 14.6 months (range, 5 to 31 mo). No cysts were observed in the ipsilateral and contralateral kidneys during follow-up. Partial and total nephrectomy was performed in 8 and 1 patient, respectively. Grossly, the cystic lesions were not discrete and merged imperceptibly with the adjacent renal parenchyma without a discrete margin or capsule. Microscopically, cystic lesions involved renal papillae in all cases, and the cystic space was continuous with dilated collecting ducts. Cysts were lined with cuboidal or flat epithelial cells identical to those lining the collecting ducts. Significant inflammation was absent. The surrounding renal parenchyma was normal. With this study, we hope to raise awareness among surgical pathologists of this rare cystic lesion in order to avoid potential misdiagnosis of this lesion as a cystic neoplasm or hereditary polycystic disease. We also presented a diagnostic algorithm for working up the renal cystic lesions.