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Venous invasion (VI) is a powerful prognostic factor in colorectal cancer (CRC) that is widely underreported. The ability of elastin stains to improve VI detection is now recognized in several international CRC pathology protocols. However, concerns related to the cost and time required to perform and evaluate these stains in addition to routine hematoxylin and eosin (HE) stains remains a barrier to their wider use. We therefore sought to determine whether an elastin trichrome (ET) stain could be used as a "stand-alone" stain in CRC resections, by comparing the sensitivity, accuracy, and reproducibility of detection of CAP-mandated prognostic factors using ET and HE stains. Representative HE- and ET-stained slides from 50 CRC resections, including a representative mix of stages and prognostic factors, were used to generate 2 study sets. Each case was represented by HE slides in 1 study set and by corresponding ET slides from the same blocks in the other study set. Ten observers (3 academic gastrointestinal [GI] pathologists, 4 community pathologists, 3 fellows) evaluated each study set for CAP-mandated prognostic factors. ET outperformed HE in the assessment of VI with respect to detection rates (50% vs. 28.6%; P0.0001), accuracy (82% vs. 59%, P0.0001), and reproducibility (k=0.554 vs. 0.394). No significant differences between ET and HE were observed for other features evaluated. In a poststudy survey, most observers considered the ease and speed of assessment at least equivalent for ET and HE for most prognostic factors, and felt that ET would be feasible as a stand-alone stain in practice. If validated by others, our findings support the use of ET, rather than HE, as the primary stain for the evaluation of CRC resections.

Background: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT. Methods: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis. Results: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2–7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4–8.9) on multivariable and IPTW sensitivity analyses. Conclusions: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.

Purpose: Stem cell markers play a significant role in esophageal adenocarcinoma carcinogenesis via Barrett’s esophagus; however, its utility as a prognostic biomarker has not been established. Methods: We analyzed the immunohistochemical expression of Ascl2 and Lgr5 utilizing whole slides (WS; 35 cases) and tissue microarray (TMA; 64 cases of esophageal adenocarcinoma with adjacent normal squamous epithelium, Barrett's esophagus, and dysplasia). Two pathologists semi-quantitatively scored stained slides independently/blindly, and the results were correlated with clinicopathologic factors and outcomes. Results: In WS, 51% and 57% expressed high Ascl2 and high Lgr5; in TMA, 69% and 88% expressed high Ascl2 and high Lgr5, respectively. In TMA, high Ascl2 and low Lgr5 expression significantly correlated to a higher number of involved lymph nodes (p=0.027 and p=0.0039), and Lgr5 expression significantly correlated to the pathological stage (p=0.0032). Kaplan-Meier analysis showed a negative impact of high Ascl2 expression on overall survival (OS; WS p=0.0168, TMA p=0.0276) as well as progression-free survival (PFS; WS p=0.000638, TMA p=0.0466), but not Lgr5. Multivariate Cox regression analysis revealed that Ascl2 expression is an independent prognostic factor for esophageal adenocarcinoma (OS; WS p=0.25, TMA p=0.011. PFS; WS p=0.012, TMA p=0.038). Analysis of the TCGA dataset showed that ASCL2 mRNA levels were correlated to nodal status but not overall survival.Conclusion: Intestinal stem cell marker, Ascl2 is an independent prognostic factor in esophageal adenocarcinoma. High Ascl2 levels were associated with nodal status in both immunohistochemical and mRNA expression. These findings may contribute to the development of prognosis-based subclassification of esophageal adenocarcinoma.

PURPOSE The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient’s sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group ( P > .12). CONCLUSION This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.

Here, we discuss recent updates and a continuing controversy in the diagnosis and management of Barrett's esophagus, specifically the recommendation that the irregular Z-line not be biopsied, the diminished status of ultrashort-segment Barrett's esophagus, the evidence basis for excluding and including the requirement of goblet cells for the diagnosis of Barrett's esophagus, and the conclusion that histologically confirmed low-grade dysplasia is best managed with endoscopic ablation rather than surveillance. We reference the American Gastroenterological Association and College of Gastroenterology and the British Society of Gastroenterology guidelines throughout, with the thesis that the field is converging on the concept of applying scarce medical resources to the diagnosis, surveillance, and therapy of patients most likely to derive benefit.

This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.

BackgroundWith a dismal 8% median 5-year overall survival (OS), pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Only 10-20% of patients are eligible for surgery, and over 50% of these will die within a year of surgery. Identify molecular predictors of early death would enable the selection of PDAC patients at high risk.MethodsWe developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors where gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework based on the binary gene pair method to create gene expression barcodes robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic datasets to date, we show that PCOSP is a robust single-sample predictor of early death (≤1 yr) after surgery in a subset of 823 samples with available transcriptomics and survival data.ResultsThe PCOSP model was strongly and significantly prognostic with a meta-estimate of the area under the receiver operating curve (AUROC) of 0.70 (P=1.9e-18) and hazard ratio (HR) of 1.95(1.6-2.3) (P=2.6e-16) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathological parameters and molecular subtypes. Over-representation analysis of the PCOSP 2619 gene-pairs (1070 unique genes) unveiled pathways associated with Hedgehog signalling, epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) signalling.ConclusionPCOSP could improve treatment decision by identifying patients who will not benefit from standard surgery/chemotherapy and may benefit from alternate approaches.AbbreviationsAUROCArea under the receiver operating curveGOGene annotationOSOverall survivalPCOSPPancreatic cancer overall survival predictorPDACPancreatic ductal adenocarcinomaTSPTop scoring pairs.

We aimed to assess current treatment patterns and outcomes in elderly patients with localized gastric and esophageal (ge) cancers. This retrospective analysis considered patients 75 years of age or older with ge cancers treated during 2012&ndash, 2014. Patient demographics and tumour characteristics were collected. Overall survival (os) and disease-free survival were assessed by univariable and multivariable Cox proportional hazards regression, adjusting for demographics. Logistic regression analyses were used to examine factors affecting treatment choices. The 110 patients in the study cohort had a median age of 81 years (range: 75&ndash, 99 years). Primary disease sites were esophageal (55%) and gastric (45%). Treatment received included radiation therapy alone (29%), surgery alone (26%), surgery plus perioperative therapy (14%), chemoradiation alone (10%), and supportive care alone (14%). In multivariable analyses, surgery (hazard ratio: 0.48, 95% confidence interval: 0.26 to 0.90, p = 0.02) was the only independent predictor for improved os. Patients with a good Eastern Cooperative Oncology Group performance status (p = 0.008), gastric disease site (p = 0.02), and adenocarcinoma histology (p = 0.01) were more likely to undergo surgery. At our institution, few patients 75 years of age and older received multimodality therapy for localized ge cancers. Outcomes were better for patients who underwent surgery than for those who did not. To ensure optimal treatment selection, comprehensive geriatric assessment should be considered for patients 75 years of age and older with localized ge cancers.

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours. Funding sources for this study include grants to the Pancreatic Cancer Sequencing Initiative program from the Ontario Institute for Cancer Research (OICR), through support from the Ontario Ministry of Research and Innovation, the Canada Foundation for Innovation; research award to F.N. from the OICR and the Canadian Institutes for Health Research (CIHR); Canadian Friends of the Hebrew University, the SMGS Family Foundation, NCI grant P50 CA102701 (Mayo Clinic SPORE in Pancreatic Cancer) and NCI grant R01 CA97075 (Pancreatic Cancer Genetic Epidemiology Consortium). F.N. is supported by a fellowship award from CIHR and is a recipient of a scholar’s research award from the Ontario Institute of Cancer Research (OICR), through support from the Ontario Ministry of Research and Innovation. G.Z. is a Clinician–Scientist of the Fonds de la Recherche en Sante du Quebec. P.J.C. is a Wellcome Trust Senior Clinical Fellow. T.J.H., L.D.S., J.D.M. and S.G. are recipients of Senior or Clinician–Scientist Awards from the Ontario Institute for Cancer Research

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Contains fulltext : 193579.pdf (Publisher’s version ) (Closed access) BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0.97 for colon tumour; r=0.97 for invasive margin; p

We integrated clinical, genomic and transcriptomic data from 217 primaries and 101 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma. Driver genes alterations, mutational and expression-based signatures were mostly preserved, and discordances implied Halstedian tumour spread. Cell cycle progression increased with sequential inactivation of tumour suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene mutations. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Inter-tumoural heterogeneity showed conserved truncations, inversions and translocations and therefore likely driver events. Multiple synchronous and metachronous PDAC arising in the same patients were actually intra-parenchymal metastases, and not independent primary tumours. Established clinical co-variates dominated survival analyses, though cell cycle progression, hypoxia and inter-tumoural heterogeneity may inform clinical practice.

BackgroundTraditional serrated adenoma (TSA) is a very characteristic type of serrated polyp that has a predilection for the left colon. Recent molecular advances have shown two molecular phenotypes of TSA: one associated with BRAF mutations and the other with KRAS mutations. The former is associated with hyperplastic polyps (HPs) and sessile serrated adenomas (SSAs), while the latter is associated with more conventional adenomatous dysplasia.AimsThe association of TSAs with so-called precursor lesions (HPs and SSAs) is not well recognised and the purpose of this study was to explore the coexistent presence of HPs, SSAs and adenomatous polyps within a large cohort of TSAs.MethodsIn total 149 TSAs were examined for the presence of HP, SSA and adenomatous polyps.ResultsSeen in 83 men and 65 women ranging in age from 32 to 89 years and 127 were left sided with 22 in the right colon. Seventy-eight of the 149 TSAs showed evidence of another polyp (52.34%): 32 were low-grade tubular/tubulovillous adenomas (TAs/TVAs; 41%), 28 were HPs (36%) and 18 were SSAs (23%). Eleven of the 22 right-sided TSAs were associated with a precursor lesion (1 HP and 7 SSA). In addition, five TSAs showed more than one polyp type: TSA with TA/TVA and HP (3); TSA with TA/TVA and SSA (2). The TAs/TVAs were adjacent to the TSA but occurred as a separate discrete polyp, while HPs and SSAs were intermingled with the TSA and present at the base and surface of the lesion.ConclusionsMore than 50% of TSAs are associated with a precursor lesion or adjacent TA/TVA. Their recognition is important as this may have surveillance and management ramifications.

Aims To ascertain the degree of histological overlap between conventional villous/tubulovillous (VA/TVAs) and traditional serrated adenomas (TSA). Methods and results A total of 180 polyps from the left colon/rectum diagnosed as VA/TVAs were retrieved randomly and reviewed by five pathologists looking specifically at luminal serration, cytoplasmic eosinophilia and the presence of ectopic crypt foci (ECF). For comparative purposes, 100 tubular adenomas and 80 TSAs were also examined. Twenty VA/TVAs were reclassified as TSA. Luminal serration as noted in TSA was not seen in any of the remaining 160 polyps, ECFs were noted in 55 of the 160 VA/TVAs (34%), while cytoplasmic eosinophilia (constituting

Aims Traditional serrated adenomas (TSAs) account for 5% of serrated polyps, and have a villiform architecture, eosinophilic cells with a brush border, and indented, flat‐topped luminal serrations. However, some are composed of mucin‐filled goblet cells (GCs): mucin‐rich TSA (MrTSA). The aim of this study was to determine whether this variant has unique features as compared with classic TSA (cTSA). Methods and results One hundred and fifty‐six TSAs were retrieved from the period 2010–2016. Patient demographics, site of polyps and 16 microscopic variables were evaluated. TSAs containing ≥50% GCs were classified as MrTSAs. Ectopic crypt foci (ECFs) were quantified as low (1–10) or high (>10), counted at ×200 magnification, and the average was taken for 10 fields. Twenty‐four fulfilled the criteria for MrTSA. In males, MrTSAs (65%) were more prevalent than cTSAs (55%). There was no age difference, and both variants had a predilection for the left colon, although, in the right colon, MrTSAs were more frequent (39%) than cTSAs (10%) (P=0.012). Adenomatous dysplasia was present in four of 24 MrTSAs (low grade, 3; high grade, 1). The most distinctive features of MrTSAs were: a variable growth pattern [endophytic (9%), mixed (30%), or villiform/exophytic (61%)], and a lower frequency of ECFs(P=0.001) and more intraepithelial lymphocytes (P95% GCs). Conclusions MrTSA is characterized by >50% GCs, and fewer ECFs than cTSA, but with preservation of archetypal luminal serrations. Awareness of this variant will prevent misdiagnosis, given the association of TSA with the accelerated pathway to colorectal cancer.

Sahar Al-Haddad,1 Hala El-Zimaity,2 Sara Hafezi-Bakhtiari,3 Shanmugarajah Rajendra,4,5,6 Catherine J. Streutker,1 Rajkumar Vajpeyi,3 and Bin Wang4,5 1Department of Laboratory Medicine, St. Michael’s Hospital and the University of Toronto, Toronto, Canada. 2Department of Laboratory Medicine and Pathology, Toronto General Hospital, Toronto, Canada. 3Department of Pathology, Toronto General Hospital and University of Toronto, Toronto, Canada. 4Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, Australia. 5South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, Australia. 6Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, Australia

Metabolic diseases could be inherited as inborn errors of metabolism or acquired. In this review we discuss some of the metabolic disorders likely to present in the adult population and in which liver biopsy could be indicated as part of diagnosis or treatment. These include iron overload/hemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency, Niemann–Pick's disease and Gaucher's disease with emphasis on characteristic or helpful histopathologic features. In this era of molecular and other non-invasive analyses, the role of liver biopsy for primary diagnosis has decreased but is still an important tool for supplementing clinical/molecular diagnosis, staging disease and as a guide to management. In addition to qualitative assessment, quantitative measurements of iron and copper per unit dry weight of liver tissue can be performed on paraffin-embedded blocks and should be considered in patients being treated for iron overload or being worked up for possible Wilson's disease respectively. Gaucher's disease and Niemann–Pick's disease are examples of lysosomal storage diseases that could present outside of the pediatric population; these diseases have fairly distinguishing features that could be used to triage which patients need additional enzyme or other assays for definitive diagnoses. While non-alcoholic steatohepatitis remains the commonest metabolic liver disease in adult population, the pathologist should also be aware of these other entities discussed in this review.

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.

Despite great advances in treatment of liver disease, liver transplant remains the only cure for end stage liver disease and hepatocellular carcinoma. Successful management of immediate and intermediate post-transplant events determines the overall graft outcome, and pathologists play a key role in achieving long-term graft survival. In evaluating liver allograft biopsies, bile duct changes frequently pose diagnostic dilemma as they could occur in association with or the result of various causes of graft dysfunction, but in which accurate classification and interpretation is key to subsequent management. The approach to interpreting these changes share some similarity to the non-transplant liver biopsy interpretation but several additional factors come into play in transplant setting sometimes making interpretation more complex. This review describes bile duct changes occurring in association with various clinical entities in liver allografts, such as acute and chronic rejection, obstruction, small-for-size syndrome, recurrent biliary diseases, and recurrent fibrosing cholestatic hepatitis C, and others, and discusses an approach to interpreting and reporting them.

145 Background: Central nervous system (CNS) metastases (mets) in gastroesophageal (GE) cancers are rare. There have only been limited studies examining the role of HER2 status in CNS mets in GE cancers. Methods: A retrospective analysis was performed for patients (pts) treated for GE cancers at the Princess Margaret Cancer Centre from 2011-2016. Quantitative and qualitative data were collected for all pts with CNS mets. Kaplan-Meier method was used to calculate overall survival (OS) and CNS progression free survival (PFS) for CNS mets pts. Results: Of 34 GE cancer pts diagnosed with CNS mets, 11 were HER2+, 11 HER2- and 12 had unknown HER2 status. Median time from initial cancer diagnosis to CNS mets was 10.3 months (13.4 in HER2+, 5.8 in HER2-, 11.7 in HER2 unknown). Characteristics at CNS mets diagnosis included: median age 63; 85% male; 74% had extracranial systemic mets; performance status ECOG 0-1 (64%), 2 (12%), 3-4 (24%). Treatment for CNS mets is shown in Table 1. Median OS from diagnosis of CNS mets was 6.1 months (95%CI 3.2-16.4) for all pts, 17.1 (95%CI 9.9-NA) in HER2+, 1.8 (95%CI 0.6-NA) in HER2-, 6.0 (95%CI 1.9-NA) in HER2 unknown, p=0.01. Median OS from initial cancer diagnosis was 18.5 months (95%CI 13.6-33.7) for all pts, 28.9 (95%CI 21.32-NA) in HER2+, 10.8 (95%CI 6.37-NA) in HER2-, 18.6 (95%CI 10-NA) in HER2 unknown, p=0.015. The 1 year CNS PFS rate was 35% (95%CI 22.1 – 55.5%) for all pts, 53% (95%CI 29.9 – 94%) in HER2+, 18.2% (95%CI 5.3 – 63.7%) in HER2-, 33% (95%CI 15 – 74.2%) in HER2 unknown, p=0.053. Conclusions: HER2+ pts tended to develop CNS mets later than HER2-. HER2+ pts were more likely to receive CNS-directed interventions, with more HER2+ pts having surgery for CNS mets while more HER2- had supportive care. This analysis is the first to suggest that in pts with CNS mets, HER2+ pts had longer survival than HER2-, both from initial diagnosis and after developing CNS metastases.[Table: see text]

147 Background: Literature on recurrence and outcomes of HPGEC is scarce. The aim of this study was to determine pattern of recurrence and outcomes after curative intent surgery for locally advanced HPGEC. Methods: A retrospective database was used to identify consecutive patients with gastroesophageal adenocarcinomas undergoing curative intent resection between 2011 and 2016 at the Princess Margaret Cancer Centre. Clinico-demographic data were extracted from the electronic health record. Patterns of relapse are classified as nonvisceral (defined as recurrences in the bone, peritoneal or both), visceral (not nonvisceral, including the brain), or both. Time to relapse (TTR) and overall survival (OS) were calculated from date of histologic diagnosis. Results: Of 45 patients with HPGEC, 78% were male, and 91% were non-Asian. Median age was 64.4 years (interquartile range [IQR] 53, 70); 60% were gastroesophageal junction, 24% were gastric, and 16% were esophageal adenocarcinomas; 31% were poorly differentiated tumors while 68% had clinical or pathological node positive disease. Complete R0 resection occurred in 93%, and 84% had received perioperative therapy (31% with perioperative chemotherapy; 40% with pre-operative chemoradiation; 9% with post-operative chemoradiation). With a median follow-up time of 26.0 months. relapse rate of HPGEC at last follow-up was 78%. Among first relapses, 94% were distant, while 6% were local recurrences. Among distant relapses, visceral recurrences occurred in 85%, nonvisceral in 3%, and 12% patients had both visceral and nonvisceral recurrences. None had peritoneal only recurrence. Median TTR was 12.2 months (IQR 8.8, 23.5), while median post-recurrence survival was 9.7 months (IQR 4.7, 16.3). Of the entire cohort, 2-year OS was 53% and 3-year OS was 26%. Conclusions: More than three-quarters of patients with HPGEC experienced recurrence after curative intent multimodality therapy. Our results suggest that HPGEC rarely relapse with peritoneal only disease or local recurrence, thereby calling into question the utility for aggressive surveillance, pending verification from larger cohorts.

148 Background: In gastric/GEJ cancer, 40% of patients (pts) are metastatic at diagnosis ( de novo stage IV) and up to 70% with locoregional disease recur (relapsed stage IV). We compared survival outcomes between de novo vs relapsed stage IV. Methods: A retrospective observational study of stage IV gastric/GEJ pts was conducted (2012-2015). Overall survival (OS) was from date of stage IV diagnosis. PFS1 defined the period from stage IV diagnosis to first progression. PFS2 was from first to second progression. For relapsed stage IV pts, disease-free interval (DFI) was the period from initial diagnosis to metastatic relapse. Cox proportional hazards models compared OS, PFS1 and PFS2 between de novo vs relapsed stage IV pts, stratified by DFI [ < 6, 6-12 and > 12 months (mo)] and controlled for baseline patient characteristics. Results: Of 198 pts, 62% were male and median age was 64 years (26-93), with 64% gastric and 36% GEJ adenocarcinomas. Primary therapy for locoregional pts included surgery (75%), perioperative chemotherapy (42%) and radiotherapy (42%). De novo and relapsed stage IV pts represented 68% and 32% of the cohort respectively. Median follow-up was 13 mo. Controlled for age, performance status and Charlson comorbidity index, there were no significant differences in OS (median OS 12.5 ( de novo) vs 12.2 mo (relapsed); HR 1.22, 95% CI 0.83-1.77, p = 0.31), PFS1 (6.8 vs 7.4 mo; HR 1.00, 95% CI 0.65-1.56, p = 0.98) or PFS2 (3.8 vs 3.0 mo; HR 1.03, 95% CI 0.44-2.41, p = 0.95). Median OS for relapsed stage IV patients were different by DFI groups (log-rank p = 0.02): 22.9 mo (for DFI > 12mo; n = 31), 11.2 mo (DFI 6-12; n = 19) and 7.5 mo (DFI < 6; n = 14). Additionally, OS was significantly better if the DFI was greater than 12 mo, compared with de novo stage IV (HR 0.50, 95% CI 0.28-0.88, p = 0.02). Conclusions: There was no observed difference in the natural history of de novo vs relapsed stage IV gastric/GEJ pts. DFI was strongly prognostic with median OS (from date of relapse) approaching 2 years for relapsed pts with DFI > 12 mo. In addition to implications for treatment strategy, tumor biology within subgroups should be examined to identify novel biomarkers and potential therapeutic targets.

131 Background: The landmark ToGA trial established trastuzumab (T) based therapy as the standard of care for advanced HER2+ gastric and gastroesophageal junction cancer. However, outcomes for T based therapy for HER2+ esophageal cancer have not been well characterized. Methods: We conducted a retrospective analysis of patients (pts) with HER2+ gastroesophageal cancer receiving T based therapy at our institution from 2011-2016. Distal esophagus ( < 35 cm) and Siewert type I/II tumours were defined as esophageal (E). Siewert type III and stomach tumours were defined as gastric (G). Trained abstractors collected pt demographics and treatment details. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of first T treatment. Chi-square tests, t-tests and Cox proportional hazards models were applied where appropriate. Results: We identified 87 pts with advanced HER2+ disease. 62% (n = 54) had de novo metastatic (M1) disease. 57 patients were treated with T based therapy, with median age 57 years (IQR 48-67), 91% baseline performance status 0-1, 19% female, and 7% Asian. 63% (n = 36) had E and 37% (n = 21) had G primary tumours. 67% (n = 38) presented with M1 disease. 33% (n = 19) underwent surgery with curative intent and received T based therapy at recurrence. Baseline characteristics were balanced between the E and G groups. Survival data were available for 51 patients. The E and G groups did not have significant differences in PFS (median 9.5 vs. 9.1 months, HR 0.89 (95% CI 0.44-1.80), p = 0.74) or in OS (median 15.8 vs. 14.2 months, HR 0.88 (95% CI 0.42-1.82), p = 0.73). 63% (n = 36) were treated with subsequent systemic therapy after progression on T, with 23 receiving one line, 9 receiving two lines and 4 receiving three additional lines of treatment. The number subsequent therapies received was similar between E and G groups. Conclusions: Although patients with distal esophagus tumours were not included in the ToGA trial, our analysis suggests that patients with E and G tumours had similar outcomes. Our contemporary cohort had comparable survival outcomes relative to patients receiving T in the ToGA trial (median PFS = 6.7 months, median OS = 13.8 months).

76 Background: Perioperative chemotherapy plus surgical resection is a standard of care for locally advanced gastric or gastroesophageal junction (GEJ) cancers. There is a wide range in tumor response following cisplatin-containing preoperative chemotherapy. We investigated the relationship between tumor platinum levels and pathological tumor responses in gastric or GEJ cancer patients following preoperative chemotherapy. Methods: Tumor and adjacent normal tissues were retrieved. Pathological responses were assessed per standard criteria. Tissue platinum concentrations were determined with high-performance liquid chromatography mass spectrometry. Platinum distribution in tissue components was evaluated with imaging mass cytometry. Tissue collagen content was evaluated using trichrome staining. Results: Ten patients were enrolled in this study. Nine patients received 3 cycles of preoperative chemotherapy and 1 received 2 cycles. The median cumulative cisplatin dose was 166.8 mg/m2 (range: 95.9–181.1 mg/m2). Surgery was performed at a median time of 49 days (range: 28–72 days) after the last cycle of chemotherapy. The mean platinum level in tumor tissue in patients with any response was 893 ± 460 pg, significantly higher than in those with no response [38.8 ± 8.8 pg (p = 0.007)]. The collagen content was significantly higher in patients with any response than in those with no response (37.4 ± 6.8% vs. 11.5 ± 8.6%, p < 0.05). Platinum preferentially bound to collagen. Conclusions: Platinum was detectable in surgical specimens up to 72 days after preoperative chemotherapy. Higher tumor platinum concentration correlated with improved pathological response. Collagen binding potentially explained the high interpatient variability in tumor platinum concentrations.

122 Background: There are no phase 3 trials comparing definitive chemoradiation (bimodality) versus. perioperative chemoradiation (trimodality) for locoregional esophageal/GEJ cancer. Methods: A retrospective analysis (2011-2015) compared bimodality and trimodality therapy in patients (pts) with locoregional esophageal/GEJ cancer treated with curative intent. Overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis. Uni- and multivariable Cox proportional hazards regression adjusted for patient and disease factors. Results: Of 108 patients, 82 (76%) were male. Mean ages were 69.5 ± 11.0 years (bimodality; N = 41) and 60.5 ± 11.1 years (trimodality; N = 67). For bimodality pts, 37% had adenocarcinoma and 63% had squamous cell carcinoma (SCC). For trimodality pts, 79% had adenocarcinoma and 21% had SCC (p < 0.0001). Bimodality pts received a higher radiation dose compared to trimodality pts (50.1 ± 6.7 vs. 45.2 ± 6.4 Gy). Median follow-up was 49.3 months. We found no significant OS difference between bimodality (27.0 months) and trimodality therapy (29.8 months) in the overall cohort (p = 0.57) (4 year OS rate: 42% vs. 38%). In the subgroup with adenocarcinoma histology, trimodality therapy significantly improved OS and DFS compared to bimodality (OS: 31.8 vs. 10.4 months, hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.18-0.66, p = 0.001; DFS: 15.0 vs. 6.7 months; HR 0.39, 95%CI 0.21-0.73, p = 0.003). In the SCC subgroup, median OS and DFS were similar (OS: not reached vs. 29.2 months, p = 0.48; DFS: 27.0 vs. 24.0, p = 0.96). Using multivariable regression with AIC backward selection, the only retained prognostic factors were treatment modality (p = 0.06) and histology (p = 0.01). Conclusions: Our findings support preferential use of trimodality therapy for pts with adenocarcinoma histology given superior OS and DFS, whereas bimodality and trimodality therapy appeared comparable in pts with SCC histology. Pending confirmation in a larger series with longer follow-up, these findings suggest differential treatment algorithms for locoregional esophageal and GEJ cancer based on tumor histology.

Acute cellular rejection post liver transplant occurs most commonly but not exclusively in the first year. In this study, we report two patterns: sinusoidal infiltrative and hepatitic, which are not considered in the Banff system. We describe their presentation, response to Solu-Medrol, and compare these to the typical moderate-severe acute cellular rejection. Patients transplanted from 2007 to 2012 at University Health Network, who had biopsy-proven rejection in the first year, were studied. Baseline transaminases and bilirubin, time of acute cellular rejection, follow-up, and treatment responses were analyzed. A total of 407 biopsies were received, of which 77 had diagnosis of acute cellular rejection with rejection activity index 5 or above; 49 from viral hepatitis patients were excluded. Twenty-eight were included; 15/28 (54%) had typical acute cellular rejection (tACR) using Banff criteria. Six (21%) had hepatitic acute cellular rejection overlapping with typical features of acute cellular rejection; seven (25%) had infiltrative acute cellular rejection (iACR) overlapping with typical features. The iACR occurred later than the tACR (124 versus 50 days; P = 0.032) and had a higher rise in baseline aspartate aminotransferase (ΔAST) compared with tACR (289 U/l versus 109 U/l; P=0.046). Only one out of seven patients with iACR (14 versus 40% in tACR) failed Solu-Medrol boluses and required thymoglobulin. Patients with hepatitic acute cellular rejection (hACR) had similar ΔAST (P = 0.12) but higher bilirubinemia than typical acute cellular rejection (tACR) (160 μmol/l versus 35 mol/l; P = 0.039) and required thymoglobulin in four out of six (67% versus 40%) instances. Patients with iACR had higher ΔAST than tACR but better Solu-Medrol response compared with both tACR and hACR. hACR is different from plasma cell-rich late-occurring cellular rejection in its pattern but similar in its poor Solu-Medrol response.

10037 Background: The optimal treatment and outcome for elderly patients (pts) with localized gastroesophageal (GE) cancer remains unclear as they are underrepresented in clinical trials. We aimed to assess survival in pts ≥75 years according to treatment received. Methods: A retrospective analysis was performed for all pts aged ≥75 years with GE cancer treated in 2012-2014. Frailty was measured using the Charlson comorbidity index (CCI) and ECOG performance status (PS). Overall survival (OS) and disease-free survival (DFS) were assessed via uni- and multivariable Cox proportional hazards regression, adjusting for demographics. Logistic regression analyses were used to examine factors impacting treatment choices. Results: Of 105 pts, median age was 81 years (range: 75-99), primary sites were esophageal (55%, with 43% squamous histology) and gastric (45%). Baseline characteristics included: PS: 0 (31%), 1 (42%), 2 (16%), 3 (10%), 4 (1%); and CCI: 0 (34%), 1 (25%), 2 (19%), ≥3 (22%). Treatment received included radiotherapy alone (RT) (31%); surgery alone (29%); surgery plus adjuvant chemotherapy (chemo) and/or RT (14%); chemoradiation alone (7%) and supportive care (18%). In univariable analyses; age < 85 (p = 0.003), PS < 2 (p = 0.03) and surgery (p < 0.001) were associated with improved OS. Chemo and RT, either alone or in combination, did not significantly improve OS. In multivariable analyses; surgery (HR 0.38, 95% CI 0.21-0.70, p = 0.002) was the only independent predictor for improved OS. Patients with good PS (p = 0.01), gastric disease site (p = 0.01) and adenocarcinoma histology (p = 0.02) were more likely to undergo surgery. Conclusions: At our institution, relatively few pts ≥75 years received multimodality therapy for localized GE cancers. Those pts ≥75 years who underwent surgery had excellent outcomes, but they were well-selected. Comprehensive assessment should be considered for pts ≥75 years with localized GE cancer to ensure optimal treatment selection, particularly given the potential benefit of surgery.

126 Background: The optimal CRT regimen for neoadjuvant or definitive treatment of locoregional esophageal or gastroesophageal junctional (GEJ) cancer is uncertain. There has been no direct comparison between concurrent Cisplatin/5-FU (CF) as per the CALGB 9781 trial (50.4 Gy) or Carboplatin/Paclitaxel (CP) as per the CROSS trial (41.4 Gy). Methods: A retrospective analysis comparing CF and CP was performed in all patients (pts) with locoregional esophageal or GEJ cancer treated in 2012-2014. Overall survival (OS) and disease-free survival (DFS) were assessed via uni- and multivariable Cox proportional hazards regression, adjusting for age, performance status and Charlson comorbidity index. Pathological complete response (pCR) rates were compared using Fisher’s exact test. Results: 64/86 (74%) pts were male. Median age was 64 years (range: 34-84). Primary sites were esophageal (56%, with 60% squamous histology) and GEJ (44%, with 11% squamous). 22 pts received CRT in 2012 (100% CF), 33 pts in 2013 (58% CF, 42% CP) and 31 pts in 2014 (16% CF, 84% CP). Surgery was undertaken in 19 (41%) CF and 27 (68%) CP pts. Median follow-up was 38 months. We found no significant OS difference between CF and CP overall (HR 0.82, 95% CI: 0.43-1.56, p = 0.55) or in the subgroup having surgery (n = 46; HR 2.01, 95% CI: 0.62-6.55, p = 0.25). However, in the subgroup without surgery (n = 40), CF (n = 27) was superior to CP (n = 13)(HR 0.11, 95% CI: 0.03-0.38, p < 0.001). OS was similar by histology (adenocarcinoma/squamous) in all-comers (p = 0.96), and in CF (p = 0.66) and CP subgroups (p = 0.66). DFS results were similar to OS. There was a non-significant numerical difference in pCR rates between CF (31%) and CP (18%) (p = 0.45). Conclusions: Survival is similar for CF and CP CRT regimens in patients undergoing trimodality therapy. pCR rates were comparable but lower than previously reported. In contrast, in the absence of surgical resection, CP given for CRT results in significantly inferior outcomes. Clinicians may prefer CP for surgical candidates given its toxicity profile. However, when treating with definitive CRT, CF may be preferable to CP as a standard regimen.

189 Background: The optimal treatment and outcome for elderly patients (pts) with localized gastroesophageal (GE) cancer remains unclear as they are underrepresented in clinical trials. We aimed to assess survival in pts ≥ 75 years according to treatment received. Methods: A retrospective analysis was performed for all pts aged ≥ 75 years with GE cancer treated in 2012 and 2013. Frailty was measured using the Charlson comorbidity index (CCI) and ECOG performance status (PS). Overall survival (OS) and disease-free survival (DFS) were assessed via uni- and multivariable Cox proportional hazards regression, adjusting for demographics. Logistic regression analyses were used to examine factors impacting treatment choices. Results: Of 70 pts, median age was 82 years (range: 75-98), primary sites were esophageal (40%, with 61% squamous histology), GE junction (24%) and gastric (36%). Baseline characteristics included: PS: 0 (40%), 1 (39%), 2 (14%), 3 (7%); and CCI: 0 (36%), 1 (20%), 2 (21%), ≥ 3 (23%). Treatment received included surgery (33%), radiotherapy (RT) (31%); surgery plus adjuvant chemotherapy (chemo) and/or RT (9%); chemoradiation alone (7%) and 20% had no active treatment. In univariable analysis; age < 85 (p = 0.007) and surgery (p = 0.022) were associated with improved OS. Chemo and RT, either alone or in combination, did not significantly improve OS. In multivariable analysis; age < 85 (HR 0.46, 95% CI: 0.23-0.94, p = 0.034), surgery (HR 0.32, 95% CI: 0.14-0.74, p = 0.008) and CCI < 2 (HR 0.52, 95% CI: 0.27-0.99, p = 0.048) were identified as independent predictors for improved OS. Age ≥ 85 was significantly associated with omission of surgery (OR 3.61, 95% CI: 1.13-14.01, p = 0.041) but in contrast, PS ≥ 2 (p = 0.475) and CCI ≥ 2 (p = 0.939) were not predictive. Conclusions: At our institution, very few pts ≥ 75 years received multimodality therapy for localized GE cancers. Surgery was the only treatment modality associated with a significant survival advantage, and additional chemo and/or RT did not further improve OS. The only predictor for having surgery was age. Consequently, future studies should consider comprehensive assessment for surgery so that eligible elderly pts can benefit.

Aim The purpose of this survey was to ascertain reporting habits of pathologists towards sessile serrated adenomas/polyps (SSA/P). Methods A questionnaire designed to highlight diagnostic criteria, approach and clinical implications of SSA/P was circulated electronically to 45 pathologists in the UK and North America. Results Forty-three of 45 pathologists agreed to participate. The vast majority (88%) had a special interest in gastrointestinal (GI) pathology, had great exposure to GI polyps in general with 40% diagnosing SSA/P at least once a week if not more, abnormal architecture was thought by all participants to be histologically diagnostic, and 11% would make the diagnosis if a single diagnostic histological feature was present in one crypt only, while a further 19% would diagnose SSA/P in one crypt if more than one diagnostic feature was present. The vast majority agreed that deeper sections were useful and 88% did not feel proliferation markers were useful. More than one-third did not know whether, or did not feel that, their clinicians were aware of the implications of SSA/P. Conclusions 98% of pathologists surveyed are aware that SSA/P is a precursor lesion to colorectal cancer, the majority agree on diagnostic criteria, and a significant number feel that there needs to be greater communication and awareness among pathologists and gastroenterologists about SSA/P.

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

ARID1A/BAF250a has been recently implicated as a tumor suppressor in gastric cancer. We sought to clarify the clinical significance of BAF250a/ARID1A in relation to other clinical parameters and relevant biomarkers in gastric carcinoma. Cases from 2 separate cohorts of patients with gastric carcinoma from Vancouver (n = 173) and Toronto (n = 80) were selected for the construction of tissue microarrays, which were used to assess the immunohistochemical status of BAF250a (anti-ARID1A), mismatch repair proteins and p53, as well as in situ hybridization for HER2 amplification and Epstein-Barr virus infection. The Toronto cohort contained a higher proportion of early stage cases (P = .019) and a smaller proportion of cases from the proximal stomach (P < .001). Overall, immunohistochemical loss of BAF250a was observed in 22.5% of gastric adenocarcinomas from the Vancouver group and 20% from Toronto. In both cohorts, loss of BAF250a was positively associated with loss of mismatch repair protein expression (P < .0001 and P = .035, respectively). Loss of BAF250a expression was independently associated with poor overall survival in the Toronto cohort (P = .0015), whereas no significant association with survival was observed in the Vancouver cohort. BAF250a loss was not significantly associated with any additional clinical parameters in either cohort. HER2 amplification was confirmed as a negative prognostic factor in both cohorts. These findings suggest that ARID1A/BAF250a may be of prognostic significance in a subset of patients with early stage gastric cancer and that pathological assessment should increasingly use a multimarker approach.

A 46-year-old woman had a 4-month history of progressive cough, dysphagia, and dysphonia. Laryngoscopy revealed left vocal cord paralysis, and computed tomography demonstrated a mediastinal mass arising from the thyroid and invading the trachea and esophagus (Figure 1). A biopsy of the mass revealed papillary thyroid carcinoma (PTC). The patient underwent bilateral neck dissections and total thyroidectomy with en bloc resection of the mediastinal mass with 3 cm of trachea and outer muscular layer of the esophagus. Histological examination identified PTC with regions of poorly differentiated thyroid carcinoma (PDTC) in nodal metastases and in areas of extrathyroidal extension (pT4aN1b); margins were involved. Angioinvasion was characterized by intravascular tumor cells admixed with thrombus (1). Postsurgical thyroglobulin was undetectable ( 0.9 g/L); thyroglobulin antibodies were positive (183 IU/L). Following 200 mCi of radioactive iodine, no uptake outside the neck was identified. The patient received prophylactic external beam radiotherapy to the neck and superior mediastinum. Four months after surgery, she was found to have lung metastases with increasing thyroglobulin antibodies (551 IU/L). The low-burden lung disease remained relatively stable. Sixteen months after surgery, a postcricoid esophageal stricture was diagnosed. During gastroscopy to dilate it, a 1.5-cm suspicious nodule in the proximal body of the stomach was noted and biopsied. This was metastatic PTC with areas of PDTC. Although most thyroid carcinomas encountered in visceral organs represent metastatic disease, these can also arise within teratomas and ectopic thyroid tissues (2). Anaplastic thyroid carcinoma is known to metastasize to the stomach; however, intra-abdominal metastases from PTC or PDTC are extremely uncommon (3, 4). The application of rigid criteria to diagnose vascular invasion as identified in this case provides a clinically relevant prediction of distant metastasis in patients with thyroid carcinomas (1). To the best of our knowledge, this is the first reported gastric metastasis originating from PTC with regions of PDTC.

Inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC) is reported to be mild and prone to right-side predominance with rectal sparing. However, no dedicated studies evaluating patterns of presentation of liver disease with respect to IBD are available. We performed a detailed histological examination of the colonic biopsies in the context of PSC, identifying 97 patients [89 with ulcerative colitis and ten with Crohn’s disease (CD)] stratified into two groups, based on their initial disease presentation: hepatic/biliary (group 1—PSC-IBD; n = 56) versus colonic (group 2—IBD-PSC; n = 41). Inflammatory bowel disease that preceded PSC had a tendency to have a “pan-colitis” distribution; this group included all patients with CD. Inflammatory bowel disease diagnosis that followed PSC presentation was more likely to be right-sided, sparing the descending, sigmoid and rectal regions (p = 0.002). In both groups, colitis was mild with focal deep plasmacytosis and occasional mild cryptitis. Active cryptitis with crypt abscesses, surface erosion and ulceration were not identified in any of the patients. Colitis associated with PSC shows mild disease activity and the colitis pattern is associated with disease presentation, i.e. colitis preceding PSC (IBD-PSC cohort) typically have a pancolitic distribution, while colitis following PSC (PSC-IBD cohort) demonstrates right-sided predominance. Awareness by pathologists and clinicians of these patterns of inflammatory bowel disease is important and of use in directing appropriate investigations for patients.

Background Choriocarcinoma within an ovarian carcinoma is exceptionally rare. Nevertheless, recognition of this mixed tumour is important for administration of appropriate chemotherapy. Case A 65-year-old woman underwent resection of an ovarian mass after presenting with a pelvic mass and breast tenderness. On pathologic examination the mass showed a choriocarcinoma in association with a serous carcinoma. This pathologic diagnosis led to a specific chemotherapy regimen with cisplatin, etoposide, and bleomycin, suitable for both types of malignancy. Conclusion Both gynaecologists and pathologists should be aware that the histopathologic classification of ovarian epithelial carcinoma and its variants, such as this one, may have an increasing role in the management of this disease.

A 71-year-old man presented with a slowly growing 2.0×2.0×1.0 cm scalp lesion that was surgically removed. Microscopic examination showed a well-circumscribed dermally located tumor composed of ductal elements lined by double to multiple cell layers of bland cuboidal inner cells and elongated spindled outer cells with areas showing cribriform and solid growth patterns. Some cells showed prominent cytoplasmic clearing. A few mitotic figures are noted ranging from 1-2 mitotic figure/10 hpf. There are also foci of squamous differentiation as well as occasional mature adipocytes. The background stroma was predominantly sclerotic with only small area of myxoid background (confirmed by Hale's colloidal iron). Immunohistochemical studies revealed positive immunoreactivity for EMA, CEA, CD117, HWMK, LWMK, CK7, Androgen receptor and S100 in the ductal (epithelial) cells and positive immunereactivity for calponin, SMA, CK 5/6 and p63 in the myoepithelial component. No immunoreactivity for Brst-2, ER, PR and CK20 was noted. MIB-1 showed mildly increased proliferrative index highlighting 5% of the nuclei. The overall morphology and immunohistochemical profile are that of a benign cutanoues mixed tumor (chondroid syringoma). Given the unusual striking celluarlity, we suggest to subclassify this as a hyper-cellular variant. Hafezi-Bakhtiari S, Al Habeeb A, Ghazarian D. Benign mixed tumor of the skin, hypercellular variant: a case report.

Pathologists continue to play important roles in the management of solid organ allografts. These organs experience the same diseases in the corresponding non-transplant organs, but the added context of immunosuppression and alloimmunity introduces several unique factors that the pathologist has to take into context while evaluating biopsies from this group of patients. This introduction to the current miniseries highlights these special considerations and discusses the factors that differentiate transplant biopsy from other scenarios, with a view to emphasizing their importance as they enhance the pathologist's ability to obtain and provide optimum information from allograft biopsies.