210A ANNUAL MEETING ABSTRACTS Results: Strictures were characterized by a mean 2.3-fold increase in overall mural thickness and by 2.6- and 1.8-fold increases in the areas occupied by smooth muscle and Genitourinary Pathology collagen, respectively. Approximately half the increase in wall thickness was attributable to a mean 22-fold expansion of the muscularis mucosae (MM) from 2.2±1.6% to (including Renal tumors) 16.5±10.1% of the total mural thickness and the remainder of the increase to expansions of the internal layer of muscularis propria (MP-I) and submucosa (SM). The external 845 PTEN and p27 Loss Differ Among Morphologic Patterns of layer of the muscularis propria was similar in thickness and composition to controls. Prostate Cancer Microscopically, the expanded MM featured (1) architectural disarray, (2) myocyte Daniel W Abbott, Shira Ronen, Amrou Abdelkader, Anjishnu Banerjee, Yayun Xu, hyperplasia and (3) pericellular collagen fibers. In contrast, the thickened MP-I featured Oleksandr Kravtsov, Ken A Iczkowski. Medical College of Wisconsin, Milwaukee, WI. (1) preserved muscular architecture, (2) no pericellular collagen fibers, and (3) widened Background: The presence and amount of cribriform prostate cancer (Cribr.) versus intramuscular septa with increased collagen. The SM exhibited fibrosis in continuity other Gleason 4 cancer are associated with increased recurrence (PMID:21685037) with the intramuscular septa. Additionally, submucosal arteries and veins frequently and cancer death (PMID:25189638). PTEN loss inactivates cell cycle inhibitor p27/ exhibited eccentric fibromuscular hyperplasia which was polarized toward the mucosa. Kip1 (PMID:11175795): both prognostically adverse events, whose correlation with Conclusions: Stricturing Crohn’s ileitis is characterized by distinctive fibromuscular morphology has not been studied in detail. alterations in the individual intestinal wall layers. These alterations may reflect Design: Selected whole slides from 46 cancer specimens with Cribr. were differential mesenchymal responses to luminal-based and transmural inflammatory immunostained (IHC) for PTEN or p27. A subset of 15 cases was studied by chromogenic stimuli. The implications for stricture pathogenesis may help guide progress toward in situ hybridization (ISH, RNAscope®, Advanced Cell Diag.) using probe to PTEN prevention and therapy. or CDKN1B (to detect p27). To analyze both IHC and ISH, for each Gleason (Gl.) morphologic subtype, 2-3 JPG 400x images were captured, and (after editing out stroma) the fraction of tumor epithelium positive was digitally assessed using Axiovision Release 844 Constrictive Strictures in Crohn’s Ileitis 4.7.1. For IHC, 0-0.1 was assigned 0, >0.1-0.4 was 1+, >0.4-0.7 was 2+, >0.7 was 3+. Xiaofei Zhang, Huai-Bin Mabel Ko, Zhenjian Cai, Hongfa Zhu, Alexandros D Statistical analysis for IHC used the Kolmogorov-Smirnov test (10 comparisons, Polydorides, Noam Harpaz. Icahn School of Medicine at Mount Sinai, New York, NY. significant if p<0.005). ISH used fixed effects for morphology and random effects for Background: Ileal strictures in Crohn’s disease (CD) classically present as segmental each patient (significant: p<0.05). regions of mural thickening, “rubber-hose” rigidity and luminal narrowing, features Results: IHC: that correspond microscopically to fibromuscular, lymphoid or neural hypertrophy and distorted mural architecture. We describe a subset of ileal CD strictures in which these Acini Mean PTEN IHC (0-3+) p features are relatively inconspicuous and where luminal narrowing results mostly from Benign 2.52 ref contracture of the intestinal wall. Gl. 3 1.88 .07 Design: In a prospective study, resected ileal strictures of 26 CD patients were serially Gl. 4- Fused 1.50 .0012 cross-sectioned along with the adjoining non-strictured bowel. Evaluation of H&E- Gl. 4 Cribr- peripheral cells 1.48 .01 (borderline) stained slides revealed a subset of strictures with reduced external circumference. For morphometric analysis we selected a specimen that contained 5 separate strictures Gl. 4 Cribr- central cells 0.90 <.0001 yielding a total of 79 cross-sections (Figure). H&E and smooth muscle actin-stained Gl. 4 Cribr- small size like benign 1.22 .0003 slides were digitally scanned at 20X and evaluated morphometrically via Halo software Gl. 5 0.80 <.0001 (Indica Labs). Results: The outer circumferences of the intestinal wall in strictured segments at their p27 loss compared to benign acini (mean 2.5+) was significant only for Cribr- peripheral narrowest points measured 58.1, 72.1, 63.0, 69.4 and 66.2% of controls. The walls (mean 1.5+, p=.0029); Fused was (p=.0075). of the strictured segments and individual muscular layers were thickened compared ISH: With PTEN, significant loss normalized to benign acini was observed for cribriform to control sections (mean 6.4±2.2 vs 3.6±0.9mm, respectively, p=0.004) but there cancer (p<0.02), but not for fused small acini or Gleason 3/separate acini. were no significant differences in the areas of the muscularis mucosae (11.3±2.0 vs. Acini Mean PTEN ISH* p 2 2 14.3±7.2mm , respectively, p=0.77) or muscularis propria (75.1±10.0 vs. 65.1±1.7mm , Benign 7.9 ref respectively, p=0.69), suggesting a net conservation of muscle mass. There was no Gl. 3 7.2 .582 histological evidence of architectural distortion of the mural layers or substantial neural or lymphoid hyperplasia. The maximal proportions of outer circumferences covered by Gl. 4- Fused 5.9 .159 mesenteric fat in the strictured and non-strictured areas were 79.8±5.6% vs. 42.5±4.9%, Gl. 4- Cribr (peripheral and central) 5.0 .019 respectively (p=0.004). *100x (Pixels of epithelium with signal/Total pixels of epithelium) With CDKN1B, the degree of signal loss in these 3 cancer morphologies was not significant. Conclusions: The uniquely adverse outcome of cribriform cancer is mirrored by greater molecular changes than in other morphologies. Cribriform structures’ peripheral cells have higher proliferation index according to prior work. PTEN loss predominates in central cells and p27 loss peripherally, suggesting that a biphenotypic population plays a role in generating cribriform growth. For PTEN loss as a prognostic factor, cribriform structures demand separate assessment in peripheral vs. central populations. 846 Non-Tumoral Parenchymal Changes in Renal Cell Carcinoma Cases Behnoush Abedi-Ardekani, Lars Egevad, Roz Banks, James D McKay, Paul Brennan, Ghislaine Scelo. International Agency for Research on Cancer, Lyon, France; Karolinska Institute, Stockholm, Sweden; University of Leeds, Leeds, United Kingdom. Background: Large, unexplained geographical variations in renal cell carcinoma (RCC) incidence rates have been observed, with the highest rates observed in the Czech Republic (CR). We explored chronic pathological changes in the non-tumoral renal cortex (CPCRC) of RCC cases from five European countries involved in the Conclusions: A subset of “constrictive” ileal strictures in CD is characterized by Cancer Genomic of the Kidney (CAGEKID) study, and their possible relationship contracture, preserved mural architecture and near-encasement by mesenteric fat. We with tumorigenesis. hypothesize that such strictures result from compression by hypertrophic mesentery, but Design: Scanned images of 626 frozen normal tissue samples distant from the tumor in cannot exclude a role for unidentified physiologic interactions between the mesentery conventional RCC cases from CR, Romania, Serbia, United Kingdom (UK) and Russia and intestinal wall. These findings support recent hypotheses regarding a primary role were read twice by one pathologist who evaluated the degrees of interstitial inflammation for the mesentery in the pathogenesis of CD. and fibrosis, tubular atrophy, golomerulosclerosis and arterial wall thickening. In the CAGEKID project, an independent systematic review of normal tissues was conducted by another pathologist to assess the level of inflammation and fibrosis with additional comments for any other specific features such as glomerulosclerosis. The agreement between these two independent observations was 89%. We used logistic regressions to analyze the association of these pathologies with clinico-pathological variables and country of residence. Results: CPCRC were observed in 116 (18.5%) of samples. Higher age was the strongest predictor (OR=1.06 for 1-year increment, 95% CI: 1.04-1.08). After adjusting for age, country was significantly associated with the presence of CPCRC. Compared to Russia, CPCRC were more common in CR (OR=2.04, 1.15-3.61) and in Romania (OR=3.56, 1.80-7.07), while no significant difference was observed with the UK and Serbia. To assess potential confounders of the association with country and sampling method, we ANNUAL MEETING ABSTRACTS 211A additionally adjusted for hypertension, presence of medulla, and type of nephrectomy 849 Programmed Death-1 (PD-1) Receptor/PD-1 Ligand (PD-L1) (partial or radical), which only marginally affected the risk estimates. Restricting the Expression in Fumarate Hydratase-Deficient Renal Cell Carcinoma analysis to cases with total absence of medulla reduced the risk estimates to 1.44 (0.77- Reza Alaghehbandan, Jan Stehlik, Kiril Trpkov, Cristina Magi-Galluzzi, Maria Pane 2.70) and 3.09 (1.33-7.15) in CR and Romania, respectively. In univariate analysis, Foix, Daniel Berney, Mathilde Sibony, Saul Suster, Abbas Agaimy, Delia Perez Montiel, tumor size was not associated with CPCRC. Kristyna Pivovarcikova, Kvetoslava Michalova, Ondrej Daum, Ondrej