Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation

Abstract

Tumor‐infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up‐to‐7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09‐6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04‐7.62; P = 0.01; up‐to‐7 HR, 3.58; 95% CI, 1.17‐10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up‐to‐7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha‐fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16‐4.91; P = 0.019; up‐to‐7 HR, 2.21; 95% CI, 1.05‐4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.

The Functional Roles of Immune Cells in Primary Liver Cancer

“…Patients lacking intratumoral mast cells showed larger tumors and higher recurrence rates, indicating the potential roles of mast cells in anti-cancer immunity. 99 Further studies are required to elucidate the roles of mast cells in the pathophysiology of liver cancer, which is important to develop novel therapeutic strategies targeting mast cells.…”

The prognostic value of an immune-related gene signature and infiltrating tumor immune cells based on bioinformatics analysis in primary esophageal cancer

“…Previous studies have revealed that mast cells had proor anti-tumorigenic roles depending on the tumor types, the stage, and localization within the tumor. Activated mast cells have been shown to be associated with poor prognosis in thyroid cancer (38), gastric cancer (39), hepatic cellular carcinoma (40), and colorectal cancer (41). Mast cell density is increased in gastric cancer, and correlated with angiogenesis, the number of metastatic lymph nodes, and patient survival (42).…”

Deciphering hepatocellular carcinoma pathogenesis and therapeutics: a study on anoikis, ceRNA regulatory network and traditional Chinese medicine

“…A reduced number of interferonproducing NK cells has been linked to advanced stages of HCC, suggesting their potential role in predicting disease prognosis (Lee et al, 2021). Furthermore, clinical observations have revealed a negative correlation between the presence of tryptase-positive mast cells and overall survival in HCC, indicating that mast cells could serve as a potential prognostic indicator for unfavorable clinical outcomes (Wang et al, 2018;Rohr-Udilova et al, 2021). Given these connections, it is crucial to thoroughly examine the function of immune cells in HCC pathology.…”