Abstract
ObjectiveTo analyze the role of frequency of heterotypic neutrophil-in-tumor structure (FNiT) in the prognosis of patients with buccal mucosa squamous cell carcinoma (BMSCC).Methods In vitro, we cocultured BMSCC cell line-H157 with neutrophils to form heterotypic neutrophil-in-tumor structures, which were then subject to fluorescence staining. Clinically, 145 patients were retrospectively enrolled. Associations between FNiT and clinicopathological variables including age, sex, smoking history, drinking history, betel nut chewing, tumor stage, node stage, metastasis, disease stage, lymphovascular invasion, extranodal extension, perineural invasion, and tumor grade were analyzed by chi-square test, and the main endpoints of interest were recurrence-free survival (RFS) and disease-specific survival (DSS) which were analyzed by the Kaplan-Meier method and Cox model.ResultsFluorescent staining results of typical heterotypic neutrophil-in-tumor structure showed that well-differentiated H157 cells had a stronger ability to internalize more neutrophils than poorly-differentiated H157 cells, with the latter often internalizing only one neutrophil or nothing. The mean FNiT was 4.2‰, with a range from 2.3‰ to 7.8‰. A total of 80 patients relapsed and 84 patients died of the disease. The 5-year RFS and DSS rate was 42% and 42%, respectively. Patients with an FNiT≥4.2‰ had a significantly higher risk for locoregional recurrence and cancer-caused death than those with an FNiT<4.2‰ (p=0.001 and p<0.001, respectively). The FNiT alone was independently significant in predicting poor RFS, and the FNiT along with tumor grade was an independent predictor for DSS.ConclusionThe FNiT as a novel predictor is significantly negatively associated with both the RFS and DSS of patients with BMSCC.
Highlights
Cell-in-cell (CIC) is an evolutionarily conserved cytobiological phenomenon [1, 2], which was first reported 150 years ago by a German scholar [3]
Fluorescent staining results of typical heterotypic neutrophil-in-tumor structure showed that well-differentiated H157 cells had a stronger ability to internalize more neutrophils than poorly-differentiated H157 cells, with the latter often internalizing only one neutrophil or nothing
The frequency of heterotypic neutrophil-in-tumor structure (FNiT) alone was independently significant in predicting poor recurrence-free survival (RFS), and the FNiT along with tumor grade was an independent predictor for disease-specific survival (DSS)
Summary
Cell-in-cell (CIC) is an evolutionarily conserved cytobiological phenomenon [1, 2], which was first reported 150 years ago by a German scholar [3]. It refers to the presence of one or more living cells within another living one and has ever since been found in varieties of tumors tissues, such as breast carcinoma [4, 5], pancreatic ductal adenocarcinoma [6], and head and neck squamous cell carcinoma (HNSCC) [7] and the like. The formation of CIC structure in tumors is a functional result of active intercellular interactions within heterogeneous tumor microenvironments, which is driven by a set of core molecular elements [16, 17] that are regulated by multiple factors, such as cholesterol and IL-8 [18,19,20,21]
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