Early gastric cancer with RhoGAP fusion is linked to frequent nodal metastasis and a part of microtubular–mucocellular histology

Introduction: Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear. Methods: We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay. Results: RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle–lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle–lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12–7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named “microtubular–mucocellular (MTMC) histology,” was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%). Conclusion: RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM.