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Background: Esophageal adenocarcinoma (EAC) is usually resistant to cytotoxic therapies and immunotherapies have gained little traction. Cancer-associated fibroblasts (CAF) are a major stromal cell population in the EAC tumor microenvironment associated with prognosis and treatment outcomes. Recent evidence suggests that cancer cell phenotypes related to EMT may determine CAF heterogeneity, but the molecular and cellular biology that underlies myofibroblast fate in EAC is not well understood. Methods: To obtain the most comprehensive profile of CAF heterogeneity in EAC, we performed histopathologic, single-cell RNA sequencing and transcriptomic analyses on 28 samples from 26 patients and prognostic validation using two EAC cohorts from genomic consortia. Results: Combining histologic and molecular profiles revealed five CAF phenotypes, including three myofibroblast phenotypes, associated with EMT-related signatures in EAC cells and cellular interactions that promote tumor progression and metastasis. We identified a specific myofibroblast subtype (CAF5) in close proximity to cancer cells and tumor vasculature with exclusive expression of TRPA1, offering a potential therapeutic vulnerability. We reconstructed CAF differentiation trajectories from esophagus-resident universal fibroblasts to identify candidate genes central to the CAF phenotype, and used this knowledge to construct a combined EMT-myofibroblast four gene signature (GSN, ATF1, ZEB2 and POSTN) that was highly prognostic in EAC and several other solid tumors. Conclusions: This study stratifies EAC patients into two prognostic groups and reports important data supporting a cancer – CAF signalling axis, promoting myofibroblastic differentiation, that may inform more effective treatment strategies.

Counting intraepithelial lymphocytes (IELs) is a key part of the assessment of duodenal biopsies. Immunohistochemistry (IHC) for CD3 can aid identification of lymphocytes in this context, but it is not evident that counts on hematoxylin and eosin (H&E) and CD3 are comparable. This study aimed to compare the IEL counts in duodenal biopsies using H&E stains and CD3 IHC, and to examine the interobserver variability. Thirty-five paired H&E and CD3 sections were reviewed by 6 pathologists who counted the number of IELs per 100 enterocytes. The counts were categorized into groups: normal (40 lymphocytes). CD3 IHC was associated with significantly higher IEL counts than H&E. Four cases with normal H&E counts had raised counts with CD3. There was moderate agreement between observers for both H&E and CD3. Lack of concordance between CD3 and H&E IEL counts suggests that counts derived from the 2 methods may not be comparable to each other and should not be considered equivalent. There was no significant improvement in interobserver variability with CD3 IHC.

Introduction: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. Materials and methods: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006–2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. Results: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73–0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73–0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. Conclusion: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant cancers. A minority (20%) of PDACs are found in the pancreatic body and tail. Accurate pathology assessment of the pancreatic specimen is essential for providing prognostic information and it may guide further treatment strategies. The recent 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/ UICC) staging system for pancreatic tumors has incorporated significant changes to tumor (pT) stage, which is predominantly based on tumor size. This change emphasizes the importance of careful block selection. Owing to the greater prevalence of tumors in the head of the pancreas, efforts are made to standardize the assessment of pancreatoduodenectomy specimens. However, consensus regarding the macroscopic assessment of distal (i.e., left) pancreatectomy specimens is lacking. The DIPLOMA approach includes the standardized measurement of pancreas and other resected organs, inking of relevant surgical margins and anatomical surfaces without removing covering layers of fat, measurement of tumor size (for T-stage), together with assessment of splenic vessel involvement (and other organs if present). All relevant margins are assessed, and relevant blocks are selected to confirm these parameters microscopically. The current protocol describes a standardized approach to the macroscopic assessment of distal pancreatectomy specimens. This approach was developed during several meetings with pathologists and surgeons during the preparation phase for an international multicenter trial (DIPLOMA, ISRCTN44897265), which focuses on radicality of distal pancreatectomy for pancreatic ductal adenocarcinoma. This standardized approach can be instrumental in the design of studies and will uniform reporting on the outcomes of distal pancreatectomy. The described technique is used in the DIPLOMA trial for pancreatic ductal adenocarcinoma but may also be useful for other indications.

Metaplastic carcinomas of the breast are a rare but morphologically heterogeneous group of tumours with a distinct immunoprofile. We describe a case of metaplastic carcinoma with mesenchymal differentiation in a patient who presented with a left breast lump. These tumours are typically composed of metaplastic cartilaginous, osseous or rhabdomyoid elements, usually with a malignant epithelial component. Here we outline the current WHO classification of metaplastic carcinomas of the breast, key clinical features and some diagnostic challenges.