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Classification of adenocarcinomas (AC) arising around or within the gastroesophageal junction (GEJ) is hampered by major morphologic and phenotypic overlaps. We reviewed the surgical pathology of esophagectomy specimens of 115 primary resected AC of the esophagus as defined by the 5th edition of the WHO classification regarding the anatomical site of the tumor, with corresponding categorization according to the Siewert AEG Classification and the preceding 4th edition of the WHO (discriminating esophageal adenocarcinomas/EAC and adenocarcinomas of the gastroesophageal junction/AdGEJ), and further histology findings. In addition, immunohistochemistry (IHC) for CDX2, CK7, CK20, MUC2, MUC5AC and MUC6 was performed. Sixty-eight cases were Siewert AEG type I and 47 cases Siewert AEG type II. Out of the AEG I tumors, 26 were classified as AdGEJ. Regardless of the classification system, more proximally located tumors showed less aggressive behavior with lower rates of lymph node metastases, lymphatic, venous and perineural invasion, better histological differentiation (p < 0.05 each) and were more frequently associated with pre-neoplastic Barrett's mucosa (p < 0.001). Histologically, the tumors displayed intestinal morphology in the majority of cases. IHC showed non-conclusive patterns with a frequent CK7+/CK20+ immunophenotype in all tumors, but also a gastric MUC5AC+ and MUC6+ phenotype in some proximal tumors. In conclusion, histology of the tumors and IHC failed to distinguish reliably between more proximal and more distal tumors. The presence of Barrett's mucosa rather than location alone, however, may help to further differentiating adenocarcinomas arising in this region and may be indicative for a particular biologic type., (© 2022. The Author(s).)

The response to neoadjuvant therapy can vary widely between individual patients. Histopathological tumor regression grading (TRG) is a strong factor for treatment response and survival prognosis of esophageal adenocarcinoma (EAC) patients following neoadjuvant treatment and surgery. However, TRG systems are usually based on the estimation of residual tumor but do not consider stromal or metabolic changes after treatment. Spatial metabolomics analysis is a powerful tool for molecular tissue phenotyping but has not been used so far in the context of neoadjuvant treatment of esophageal cancer. We used imaging mass spectrometry to assess the potential of spatial metabolomics on tumor and stroma tissue for evaluating therapy response of neoadjuvant-treated EAC patients. With an accuracy of 89.7%, the binary classifier trained on spatial tumor metabolite data proved to be superior for stratifying patients when compared with histopathological response assessment, which had an accuracy of 70.5%. Sensitivities and specificities for the poor and favorable survival patient groups ranged from 84.9% to 93.3% using the metabolic classifier and from 62.2% to 78.1% using TRG. The tumor classifier was the only significant prognostic factor (HR 3.38, 95% CI 1.40-8.12, p = 0.007) when adjusted for clinicopathological parameters such as TRG (HR 1.01, 95% CI 0.67-1.53, p = 0.968) or stromal classifier (HR 1.86, 95% CI 0.81-4.25, p = 0.143). The classifier even allowed us to further stratify patients within the TRG1-3 categories. The underlying mechanisms of response to treatment have been figured out through network analysis. In summary, metabolic response evaluation outperformed histopathological response evaluation in our study with regard to prognostic stratification. This finding indicates that the metabolic constitution of the tumor may have a greater impact on patient survival than the quantity of residual tumor cells or the stroma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort ( n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.

Background: The 8th edition of the AJCC TNM staging system presents for the first time a specific classification for esophageal carcinomas treated with neoadjuvant therapy (yTNM8). In this single center study, we applied the novel staging system in a "real life" case series and compared the prognostic value of yTNM8 with the preceding 7th edition (TNM7)., Methods: Out of 272 consecutive esophageal carcinomas that were treated during a 15-year period in one surgical center, all 198 cases that had undergone neoadjuvant therapy were reviewed and classified according to TNM7 and yTNM8., Results: 50 ypT0 cases that had no specific staging in TNM7 were included into stages I (ypT0N0M0; n = 42), IIIA (ypT0N1M0; n = 6), IVA (ypT0N3M0; n = 1) and IVB (ypT0N0M1; n = 1) in yTNM8. Both systems showed significant prognostic impact (p < 0.0001 each). yTNM8 was superior regarding prognostication with lower values for goodness-of-fit criteria (Akaike Information Criterion 1589.331 vs 1593.239; and Schwarz Bayesian Criterion 1605.487 vs.1619.088). However, in TNM7, stage IIB tumors had better prognosis than stage IIA tumors, and likewise, stage IIIA tumors better compared to stage II in yTNM8., Conclusions: yTNM8 allows accurate staging of esophageal carcinomas treated by neoadjuvant therapy, with slightly improved prognostication compared to TNM7. Additional data acquisition will be necessary for further improvement of staging for esophageal carcinomas after neoadjuvant treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Expression analysis of programmed death-ligand 1 (PD-L1) may be helpful in guiding clinical decisions for immune checkpoint inhibition therapy, but testing by immunohistochemistry may be hampered by heterogeneous staining patterns within tumors and expression changes during metastatic course. PD-L1 expression (clone SP142) was investigated in esophageal adenocarcinomas using tissue microarrays (TMA) from 112 primary resected tumors, preoperative biopsies and full slide sections from a subset of these cases (n = 24), corresponding lymph node (n = 55) and distant metastases (n = 17). PD-L1 expression was scored as 0.1-1, >1, >5, >50% positive membranous staining of tumor cells and any positive staining of tumor-associated inflammatory infiltrates and/or stroma cells. There was a significant correlation with overall PD-L1 expression between the full slide sections and the TMA (p = 0.001), but not with the corresponding biopsies. PD-L1 expression in tumor cells >1% was detected in 8.0% of cases (9/112) and 51.8% of cases (58/112) in tumor-associated inflammatory infiltrates and/or stroma cells of primary tumors. Epithelial expression in metastases was found in 5.6% of cases (4/72) and immune cell expression in 18.1% of cases (13/72), but did not correlate with the expression pattern in the primary tumor. Overall PD-L1 expression in the primary tumor did not influence survival. However, PD-L1 expression was correlated with the number of CD3 + tumor-infiltrating lymphocytes in the tumor center, and a combinational score of PD-L1 status/CD3 + tumor-infiltrating lymphocytes was correlated with patients' overall survival.

The host inflammatory response plays an important role in many solid malignancies. Studies on oesophageal adenocarcinomas (EACs) point towards a beneficial role of pronounced immunoreaction, however, congruent results have yet to be obtained. We analysed 111 primary resected EAC using a tissue microarray containing three cores of the tumour centre and the periphery per case. Overall inflammation was assessed by histomorphology. Tumour infiltrating lymphocytes (TILs) were characterised by immunohistochemistry for CD3, CD8 and FoxP3, and evaluated by image analysis (Aperio ImageScope). High levels of inflammation in the tumour centre, but not the periphery were associated with better patient survival (p = 0.001), similar to high counts of intratumoural FoxP3+, CD3+, CD8+ TILs (p = 0.001; p = 0.027; p = 0.038) and a combination of CD3+/CD8+/FoxP3+ TILs, the latter displaying three different prognostic groups (triple high/mixed/triple low; p=0.003). Intratumoural inflammation [hazard ratio (HR) = 0.432; p = 0.030], FoxP3+ TIL counts (HR = 0.411; p = 0.033) and the combination CD3+/CD8+/FoxP3+ TILs (HR = 0.173; p = 0.006) were also independent prognostic parameters. In summary, both high grade total inflammation and high TIL counts in the tumour centre, but not the tumour periphery, show a beneficial prognostic impact on EAC. This may be a target for novel therapeutic options but also serves as prognostic indicator in these tumours., (Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Esophageal adenocarcinomas (EAC) are aggressive tumors with considerable rates of chemoresistance. Autophagy is a lysosome-dependent degradation process, characterized by the formation of vesicles called autophagosomes, and has been implicated in cancer. Protein light chain 3 B (LC3B) and p62 are associated with autophagosomal membranes and degraded. We aimed to assess the impact of basal autophagy on EAC. In EAC cell lines, an increase in LC3B and p62 was observed with increasing concentrations of the autophagy inhibitor chloroquine, which indicates functional basal autophagy. LC3B and p62 immunohistochemistry was performed on primary resected EAC. High LC3B and p62 expression was associated with earlier tumor stages (p < 0.05). High nuclear and cytoplasmic p62 staining were associated with a better prognosis (p = 0.006; p = 0.028). Various combinations of p62 expression with or without LC3B expression identified different prognostic groups. Tumors with low total p62 (p = 0.007) or low LC3B/low p62 expression had the worst outcome (p = 0.007; p = 0.005). A combination score of dot-like/cytoplasmic p62 and nuclear p62 staining was an independent prognostic parameter (p = 0.033; HR = 0.6). This study highlights the potential significance of basal autophagy in EAC biology. Tumors with low LC3B and p62 expression show the most aggressive behavior and may be candidates for autophagy regulating therapeutics., Competing Interests: The authors have no conflicts of interest to declare.

Tumor budding has prognostic significance in many carcinomas and is defined as the presence of detached isolated single cells or small cell clusters up to 5 cells at the invasion front (peritumoral budding [PTB]) or within the tumor (intratumoral budding [ITB]). For esophageal adenocarcinomas (EACs), there are currently only few data about the impact of this morphological feature. We investigated tumor budding in a large collective of 200 primarily resected EACs. Pancytokeratin staining was demonstrated to be superior to hematoxylin and eosin staining for the detection of buds with substantial to excellent interobserver agreement and used for subsequent analysis. PTB and ITB were scored across 10 high-power fields (HPFs). The median count of tumor buds was 130/10 HPFs for PTB (range, 2-593) and 80/10 HPFs for ITB (range, 1-656). PTB and ITB correlated significantly with each other (r = 0.9; P < .001). High PTB and ITB rates were seen in more advanced tumor categories (P < .001 each); tumors with lymph node metastases (P < .001/P = .002); and lymphatic, vascular, and perineural invasion and higher tumor grading (P < .001 each). Survival analysis showed an association with worse survival for high-grade ITB (P = .029) but not PTB (P = .385). However, in multivariate analysis, lymph node and resection status, but not ITB, were independent prognostic parameters. In conclusion, PTB and ITB can be observed in EAC to various degrees. High-grade budding is associated with aggressive tumor phenotype. Assessment of tumor budding, especially ITB, may provide additional prognostic information about tumor behavior and may be useful in specific cases for risk stratification of EAC patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) represent a distinct and well-recognized subtype of gastric cancer with a prevalence of around 10%of all GC. In contrast, EBV has not been reported to play a major role in esophageal adenocarcinomas (EAC) and adenocarcinomas of the gastro-esophageal junction (GEJ). We report our experiences on EBV in collections of gastro-esophageal adenocarcinomas from two surgical centers and discuss the current state of research in this field. Tumor samples from 465 primary resected gastro-esophageal adenocarcinomas (118 EAC, 73 GEJ, and 274 GC) were investigated. Presence of EBV was determined by EBV-encoded small RNAs (EBER) in situ hybridization. Results were correlated with pathologic parameters (UICC pTNM category, Her2 status, tumor grading) and survival. EBER positivity was observed in 14 cases. None of the EAC were positive for EBER. In contrast, we observed EBER positivity in 2/73 adenocarcinomas of the GEJ (2.7%) and 12/274 GC (4.4%). These were of intestinal type (seven cases) or unclassifiable (six cases), while only one case was of diffuse type according to the Lauren classification. No association between EBV and pT, pN, or tumor grading was found, neither was there a correlation with clinical outcome. None of the EBER positive cases were Her2 positive. In conclusion, EBV does not seem to play a role in the carcinogenesis of EAC. Moreover, adenocarcinomas of the GEJ show lower rates of EBV positivity compared to GC. Our data only partially correlate with previous reports from the literature. This highlights the need for further research on this distinct entity. Recent reports, however, have identified specific epigenetic and genetic alterations in EBV-associated GC, which might lead to a distinct treatment approach for this specific subtype of GC in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of esophageal cancer is constantly rising and patients are often diagnosed at an advanced stage. Surgical resection, if possible, is the curative treatment of choice. However, esophagectomy for cancer is a major surgical procedure and is associated with perioperative morbidity. Preoperative staging examinations are carried out on every patient, and imaging datasets contain valuable information about the patient's physical condition beyond the routinely assessed tumor extent. In this study, the abdominal muscle and fat mass were quantified during the preoperative staging and postoperative follow-up of 85 patients with locally advanced esophageal adenocarcinoma, and these imaging biomarkers were correlated with surgical complications and patient outcomes. Our analysis showed that sarcopenic patients with low muscle mass were more likely to have major complications and that hospitalization was prolonged, especially in patients with sarcopenic obesity. Low preoperative muscle mass and its decrease during the follow-up also predicted poorer overall survival. Background: To assess the impact of body composition imaging biomarkers in computed tomography (CT) on the perioperative morbidity and survival after surgery of patients with esophageal cancer (EC). Methods: Eighty-five patients who underwent esophagectomy for locally advanced EC after neoadjuvant therapy between 2014 and 2019 were retrospectively enrolled. Pre- and postoperative CT scans were used to assess the body composition imaging biomarkers (visceral (VAT) and subcutaneous adipose tissue (SAT) areas, psoas muscle area (PMA) and volume (PMV), total abdominal muscle area (TAMA)). Sarcopenia was defined as lumbar skeletal muscle index (LSMI) ≤38.5 cm2/m2 in women and ≤52.4 cm2/m2 in men. Patients with a body mass index (BMI) of ≥30 were considered obese. These imaging biomarkers were correlated with major complications, anastomotic leakage, postoperative pneumonia, duration of postoperative hospitalization, disease-free survival (DFS), and overall survival (OS). Results: Preoperatively, sarcopenia was identified in 58 patients (68.2%), and sarcopenic obesity was present in 7 patients (8.2%). Sarcopenic patients were found to have an elevated risk for the occurrence of major complications (OR: 2.587, p = 0.048) and prolonged hospitalization (32 d vs. 19 d, p = 0.040). Patients with sarcopenic obesity had a significantly higher risk for postoperative pneumonia (OR: 6.364 p = 0.018) and a longer postoperative hospital stay (71 d vs. 24 d, p = 0.021). Neither sarcopenia nor sarcopenic obesity was an independent risk factor for the occurrence of anastomotic leakage (p > 0.05). Low preoperative muscle biomarkers (PMA and PMV) and their decrease (ΔPMV and ΔTAMA) during the follow-up period significantly correlated with shorter DFS and OS (p = 0.005 to 0.048). Conclusion: CT body composition imaging biomarkers can identify high-risk patients with locally advanced esophageal cancer undergoing surgery. Sarcopenic patients have a higher risk of major complications, and patients with sarcopenic obesity are more prone to postoperative pneumonia. Sarcopenia and sarcopenic obesity are both subsequently associated with a prolonged hospitalization. Low preoperative muscle mass and its decrease during the postoperative follow-up are associated with lower DFS and OS. [ABSTRACT FROM AUTHOR]