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Simple Summary: The surgical specimen histology of esophageal and esophago-gastric junction adenocarcinomas (EA-EGJAs) classified according to the Esophageal Adenocarcinoma Study Group Europe (EACSGE) proposal, eventually combined with the pTNM stage, is an efficient indicator of prognosis, molecular events, and response to treatment. To explore if this histologic classification may be applied to endoscopic biopsies collected at the initial diagnostic workup, we compared the histology of endoscopic and matched surgical specimen tissues collected from 106 cases of EA-EGJA with no neoadjuvant therapy. Histologic classes of endoscopic biopsies and surgical specimen were coincident. Further studies will indicate if EA-EGJA biopsy provides detailed morphological/biological information "per se" for planning therapy, if biopsy histomorphology/clinical TNM crossing is as efficient as the surgical specimen histomorphology/pTNM one, to predict prognosis and to tailor therapy. Background and Objectives: The Esophageal Adenocarcinoma Study Group Europe (EACSGE) recently proposed a granular histologic classification of esophageal–esophago-gastric junctional adenocarcinomas (EA-EGJAs) based on the study of naïve surgically resected specimens that, when combined with the pTNM stage, is an efficient indicator of prognosis, molecular events, and response to treatment. In this study, we compared histologic classes of endoscopic biopsies taken before surgical resection with those of the surgical specimen, to evaluate the potential of the EACSGE classification at the initial diagnostic workup. Methods: A total of 106 EA-EGJA cases with available endoscopic biopsies and matched surgical resection specimens were retrieved from five Italian institutions. Histologic classification was performed on all specimens to identify well-differentiated glandular adenocarcinoma (WD-GAC), poorly differentiated glandular adenocarcinoma (PD-GAC), mucinous muconodular carcinoma (MMC), infiltrative mucinous carcinoma (IMC), diffuse desmoplastic carcinoma, diffuse anaplastic carcinoma (DAC), and mixed subtypes. Related risk subgroups (low-risk versus high-risk) were also assessed. The correlations of histologic classes and risk subgroups between diagnostic biopsies and surgical resection specimens were explored with Spearman's correlation test. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, true positives, true negatives, false positives, and false negatives were also calculated. Results: A strong positive correlation between biopsies and surgical specimens occurred for both histologic classes (coefficient: 0.75, p < 0.001) and risk subgroups (coefficient: 0.65, p < 0.001). The highest sensitivities and specificities were observed for MMC, IMC, and DAC (100% and 99% for all), followed by WD-GAC (sensitivity 91%, specificity 79%) and PD-GAC (sensitivity 722%, specificity 86%). The low-risk and high-risk groups presented a sensitivity and specificity of 89% and 76% (low-risk) and 76% and 89% (high-risk). Conclusions: The EACSGE histologic classification of EA-EGJAs and associated prognostic subgroups can be reliably assessed on pre-operative diagnostic biopsies. Further studies on larger and more representative cohorts of EA-EGJAs will allow us to validate our findings and confirm if the EA-EGJA biopsy histomorphology and clinical TNM staging will be as efficient as the surgical specimen histomorphology and pTNM in predicting patient prognoses and tailoring personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical behaviour of signet ring cell histology in gastric cancer has long been a subject of controversy. Recent years have underscored the pressing issue of a lack of a standardised definition for signet ring cell histology, leading to its often-ambiguous placement within broader categories associated with poor prognosis. Conversely, comparisons of signet ring cell gastric cancer have been made against a wide spectrum of non-signet ring cell cases, introducing significant heterogeneity. The primary objective of this literature search and subsequent meta-analysis was to gain a deeper understanding of signet ring cell gastric cancer. Our findings revealed that the prognosis of signet ring cell gastric cancer is intricately tied to the disease stage, yet it is also contingent on the specific comparison group employed. The variability in signet ring cell cancer's clinical behaviour may stem from the absence of a standardised definition. Therefore, it is imperative to work towards a uniform classification system for gastric cancer to enhance clarity and coherence in future research and clinical practice. Background: Conflicting results about the prognostic relevance of signet ring cell histology in gastric cancer have been reported. We aimed to perform a meta-analysis focusing on the clinicopathological features and prognosis of this subgroup of cancer compared with other histologies. Methods: A systematic literature search in the PubMed database was conducted, including all publications up to 1 October 2021. A meta-analysis comparing the results of the studies was performed. Results: A total of 2062 studies referring to gastric cancer with signet ring cell histology were identified, of which 262 studies reported on its relationship with clinical information. Of these, 74 were suitable to be included in the meta-analysis. A slightly lower risk of developing nodal metastases in signet ring cell tumours compared to other histotypes was found (especially to undifferentiated/poorly differentiated/mucinous and mixed histotypes); the lower risk was more evident in early and slightly increased in advanced gastric cancer. Survival tended to be better in early stage signet ring cell cancer compared to other histotypes; no differences were shown in advanced stages, and survival was poorer in metastatic patients. In the subgroup analysis, survival in signet ring cell cancer was slightly worse compared to non-signet ring cell cancer and differentiated/well-to-moderately differentiated adenocarcinoma. Conclusions: Most of the conflicting results in signet ring cell gastric cancer literature could be derived from the lack of standardisation in their classification and the comparison with the different subtypes of gastric cancer. There is a critical need to strive for a standardised classification system for gastric cancer, fostering clarity and coherence in the forthcoming research and clinical applications. [ABSTRACT FROM AUTHOR]