Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome.

INTRODUCTION: Transcriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC. DESIGN: We first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes. RESULTS: We identified four morphological patterns that segregated into two components ('gland forming' and 'non-gland forming') based on the presence/absence of well-formed glands. A morphological cut-off (≥40% 'non-gland forming') was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as 'classical' using RNA-Seq. CONCLUSION: Our study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

Mucin-rich variant of traditional serrated adenoma: a distinct morphological variant.

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 (P < 0.05) than in cTSAs. MrTSAs retain characteristic luminal serrations, at least focally. Inflamed MrTSAs can mimic inflammatory polyps and hamartomatous polyps (when there are >95% 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.

Regression grading in neoadjuvant treated pancreatic cancer: an interobserver study.

AIM: Several regression grading systems have been proposed for neoadjuvant chemoradiation-treated pancreatic ductal adenocarcinoma (PDAC). This study aimed to examine the utility, reproducibility and level of concordance of three most frequently used grading systems. METHODS: Four gastrointestinal pathologists used the College of American Pathologists (CAP), Evans, MD Anderson Cancer Centre (MDA) regression grading systems to grade 14 selected cases (7-20 slides from each case) of neoadjuvant chemoradiation-treated PDAC. A postscoring discussion with each pathologist was conducted. The results were entered into a standardised data collection form and statistical analyses were performed. RESULTS: There was little concordance across the three systems. The Kendall coefficient of concordance agreement scores were: CAP: 2-poor, 2-fair; Evans: 1-fair, 1-moderate, 2-good; MDA: 1-poor, 2-moderate, 1-good. Interpretation in all three grades in the CAP grading system was a source of discrepancy. Furthermore, using fibrosis as a criterion to assess regression was contentious. In the Evans system, quantifying tumour destruction using arbitrary percentage cut-offs (ie, 9% vs 10%; 50% vs 51%, etc) was imprecise and subjective. Although the MDA system generated greatest concordance, this was due to 'oversimplification' surrounding wide, arbitrarily assigned thresholds of 5% of tumour. CONCLUSIONS: All systems lacked precision and clarity for accurate regression grading. Presently the clinical utility and impact of histological regression grading in patient management is questionable. There is a need to re-evaluate regression grading in the pancreas and establish a reproducible, clinically relevant grading system.