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Introduction: Centralization of ovarian cancer treatment is associated with higher rates of optimal surgery and longer survival. However, preoperative diagnosis of ovarian cancer is challenging and some diagnoses are made incidentally after surgery. This study investigated the surgical and oncological outcomes of patients with incidental findings of borderline ovarian tumors or ovarian cancer who were centralized postoperatively and treated with a two-stage surgical procedure, and compared these with those of patients with adnexal masses of suspected malignancy who were offered a single-stage surgical procedure with intraoperative frozen section in a tertiary hospital., Methods: A database of 390 patients with adnexal masses and surgical treatment at the Bern University Hospital, Switzerland was retrospectively reviewed to identify patients with borderline ovarian tumors or ovarian cancer between 2010 and 2020., Results: Among 390 patients with adnexal masses, 223 were diagnosed with a borderline ovarian tumor or ovarian cancer. Compared with patients with suspected malignancy and a centralized single-stage surgical procedure, patients with an incidental postoperative malignancy diagnosis and a two-stage surgical procedure underwent more surgical interventions (1.3 vs. 2.1 p<.001) and had a longer time interval from diagnosis to initiation of chemotherapy (33.3 vs. 45.1 p=.005) and to completion of surgical cytoreduction (31.9 vs. 73.7 days, p<.001). However, there were no differences in the rates of complete cytoreduction (90.0% vs. 93.2%, p=.719), intraoperative (11.3% vs. 13.7%, p=.664) or postoperative (38.7% vs. 37.0%, p=.884) complication rates, and number of hospitalization days (11.1 vs. 12.0 days, p=.369). An incidental diagnosis of malignancy with postoperative referral was neither associated with an increased risk of recurrence (hazard ratio (HR) 0.8, 95% confidence interval (CI) 0.6-1.8, p=.839) nor death (HR 0.7, 95% CI 0.4-1.1, p=.113), and there was no difference in mean recurrence-free survival between the study subgroups., Discussion: Although patients with incidental findings of borderline ovarian tumors or ovarian cancer treated with a two-stage surgical procedure had a longer time to completion of surgical staging and initiation of chemotherapy, our results showed no negative impact on oncological outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Joder, Smaadahl-Wey, Zumwald, Saner, Rauh, Hofer, Wampfler, Schlootz, Rau, Christe, Solass, Imboden, Mueller and Siegenthaler.)

Lynch syndrome is an inherited tumor syndrome caused by a pathogenic germline variant in DNA mismatch repair genes. As the leading cause of hereditary endometrial cancer, international guidelines recommend universal screening in women with endometrial cancer. However, testing for Lynch syndrome is not yet well established in clinical practice. The aim of this study was to evaluate adherence to our Lynch syndrome screening algorithm. A retrospective, single-center cohort study was conducted of all endometrial cancer patients undergoing surgical treatment at the Bern University Hospital, Switzerland, between 2017 and 2022. Adherence to immunohistochemical analysis of mismatch repair status, and, if indicated, to MLH1 promoter hypermethylation and to genetic counseling and testing was assessed. Of all 331 endometrial cancer patients, 102 (30.8%) were mismatch repair-deficient and 3 (0.9%) patients were diagnosed with Lynch syndrome. Overall screening adherence was 78.2%, with a notable improvement over the six years from 61.4% to 90.6%. A major reason for non-adherence was lack of provider recommendation for testing, with advanced patient age as a potential patient risk factor. Simplification of the algorithm through standardized reflex screening was recommended to provide optimal medical care for those affected and to allow for cascading testing of at-risk relatives.

The gut microbiome consists of more than a thousand different microbes and their associated genes and microbial metabolites. It influences various host metabolic pathways and is therefore important for homeostasis. In recent years, its influence on health and disease has been extensively researched. Dysbiosis, or imbalance in the gut microbiome, is associated with several diseases. Consequent chronic inflammation may lead to or promote inflammatory bowel disease, obesity, diabetes mellitus, atherosclerosis, alcoholic and non-alcoholic liver disease, cirrhosis, hepatocellular carcinoma, and other diseases. The pathogenesis of the three most common retinal vascular diseases, diabetic retinopathy, retinal vein occlusion, and retinal artery occlusion, may also be influenced by an altered microbiome and associated risk factors such as diabetes mellitus, atherosclerosis, hypertension, and obesity. Direct cause-effect relationships remain less well understood. A potential prevention or treatment modality for these diseases could be targeting and modulating the individual's gut microbiome., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Over the years, the molecular classification of endometrial carcinoma has evolved significantly. Both POLEmut and MMRdef cases share tumor biological similarities like high tumor mutational burden and induce strong lymphatic reactions. While therefore use case scenarios for pretesting with tumor-infiltrating lymphocytes to replace molecular analysis did not show promising results, such testing may be warranted in cases where an inverse prediction, such as that of POLEwt, is being considered. For that reason we used a spatial digital pathology method to quantitatively examine CD3 + and CD8 + immune infiltrates in comparison to conventional histopathological parameters, prognostics and as potential pretest before molecular analysis., Methods: We applied a four-color multiplex immunofluorescence assay for pan-cytokeratin, CD3, CD8, and DAPI on 252 endometrial carcinomas as testing and compared it to further 213 cases as validation cohort from a similar multiplexing assay. We quantitatively assessed immune infiltrates in microscopic distances within the carcinoma, in a close distance of 50 microns, and in more distant areas., Results: Regarding prognostics, high CD3 + and CD8 + densities in intra-tumoral and close subregions pointed toward a favorable outcome. However, TCGA subtyping outperforms prognostication of CD3 and CD8 based parameters. Different CD3 + and CD8 + densities were significantly associated with the TCGA subgroups, but not consistently for histopathological parameter. In the testing cohort, intra-tumoral densities of less than 50 intra-tumoral CD8 + cells/mm 2 were the most suitable parameter to assume a POLEwt, irrespective of an MMRdef, NSMP or p53abn background. An application to the validation cohort corroborates these findings with an overall sensitivity of 95.5%., Discussion: Molecular confirmation of POLEmut cases remains the gold standard. Even if CD3 + and CD8 + cell densities appeared less prognostic than TCGA, low intra-tumoral CD8 + values predict a POLE wild-type at substantial percentage rates, but not vice versa. This inverse correlation might be useful to increase pretest probabilities in consecutive POLE testing. Molecular subtyping is currently not conducted in one-third of cases deemed low-risk based on conventional clinical and histopathological parameters. However, this percentage could potentially be increased to two-thirds by excluding sequencing of predicted POLE wild-type cases, which could be determined through precise quantification of intra-tumoral CD8 + cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jungen, Noti, Christe, Galvan, Zlobec, Müller, Imboden, Siegenthaler, Carlson, Pellinen, Heredia-Soto, Ruz-Caracuel, Hardisson, Redondo, Mendiola and Rau.)

Grossing of surgical pathology specimens is a complex task, which may be challenging to master correctly. Despite the growing use of digital technology in other aspects of surgical pathology, little has been done so far to modernize the documentation of grossing. We used a portable video camera ("GoPro") to document different grossing procedures. The video material may be used for teaching purposes or might enhance the more commonplace macroscopic description by adding another dimension. Furthermore, video documentation may encourage the discussion of upcoming clinical questions or help rectify some possible initial impreciseness., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s) under exclusive licence to International Association of Medical Science Educators 2021.)

Tumor budding is a robust prognostic parameter in several tumor entities but is rarely investigated in endometrial carcinoma. We applied the recently standardized counting method from the International Tumor Budding Consensus Conference for colorectal cancer (ITBCC) on a cohort of 255 endometrial carcinomas with known molecular profiles according to The Cancer Genome Atlas (TCGA) subgroups. Our investigation aims to clarify the potential prognostic role of tumor budding in endometrial carcinoma in contrast to other known prognostic factors, including molecular factors. In addition, the microcystic elongated and fragmented (MELF) pattern and tumor budding were compared with respect to their potential as markers for epithelial-mesenchymal transition (EMT). Tumor budding was found in n = 67 (26.3%) tumors, with a very low mean of 0.7 buds per ×20 HE field. Tumor budding was significantly associated with depth of invasion, nodal status, lymphatic invasion (each p < 0.001), grading (p = 0.004), and vascular invasion (p = 0.01). Tumor budding showed moderate inter-observer-variability with prognostic stratification irrespective of the observer (κ-value = 0.448). In multivariate analysis, tumor budding served as a significant independent prognosticator for worse outcomes in overall and recurrence-free survival (HR 2.376 and 2.736, p < 0.001), but not when the TCGA subgroups entered into the analysis. In consequence, dependency had to be clarified in the subgroup analysis for Polymerase E mutated (POLEmut), mismatch repair deficient (MMRdef), nonspecific mutation profile (NSMP), and P53 aberrant (P53abn) endometrial carcinomas. A particular impact was identified in the intermediate prognostic groups of NSMP and MMRdef carcinomas. Tumor budding outperformed the MELF pattern in single and combined prognostic information. In conclusion, the presence of tumor budding alone is a promising, robust, and easy-to-apply prognostic parameter in endometrial carcinoma. In a morpho-molecular approach, it exerts its prognostic potential in the most clinically relevant subgroups of endometrial carcinoma and serves as a good biomarker for EMT.

The immune system plays a pivotal role in the development and progression of colorectal cancer (CRC). Tumor immune rejection has been previously linked to the activation of the interferon-stimulated genes (ISG) STAT1, IRF-5 and IRF-1. Specific immunoregulatory microRNAs (miRNAs) may impact the expression of these ISG in the tumor microenvironment. In this translational study, we develop a digital image analysis protocol to identify the ISG-gene expression signature and investigate miRNA expression in the immediate environment of invading cancer cells. Digital immunophenotyping was performed using next generation tissue microarrays from 241 well-characterized CRC patients and analyzed with clinicopathological and molecular information. Active ISG signaling in the tumor stroma differentiated an immune-activated (n = 178) and a quiescent (n = 43) phenotype. The activated phenotype was associated with high counts of intratumoral CD8 + cytotoxic T-lymphocytes (CTL; p = 0.007) and expression of the immune effector molecules granzyme B ( p < 0.001) and perforin ( p = 0.020). Immune-activated tumors also showed an elevated expression of the intercellular adhesion molecule-1 (ICAM-1, p = 0.006) which may facilitate CTL infiltration. Patients with immune-activated CRC had a considerably reduced risk of developing distant metastases ( p = 0.001, OR = 0.034, 95%CI = 0.006-0.183). High expression of the immunoregulatory miR-34a and miR-93 corresponded to a 2-2.5-fold decrease of STAT1 ( p = 0.006) and IRF-1 ( p = 0.058), a feature more commonly seen in a quiescent microenvironment. Analysis of a combined ISG marker profile by digital pathology stratifies CRC patients into diametrically opposed immune phenotypes. Targeted inhibition of miRNAs within the tumor microenvironment may form a new strategy to stimulate the anti-tumoral immune response.