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Background  Cell-in-cell structures (caused by cell cannibalistic activity) have been related to prognosis of many cancers. This is the first multi-institutional study to assess the prognostic impact of cell-in-cell structures in a large cohort of early oral tongue squamous cell carcinomas (OTSCC).Methods   A total of 308 cases from five Finnish University Hospitals and from the A.C. Camargo Cancer Center, São Paulo, Brazil, were included in this study. Cell-in-cell structures were evaluated on surgical postoperative sections that stained with hematoxylin and eosin staining.Results   We found that cell-in-cell structures associated with cancer-related mortality in univariable analysis with a hazard ratio (HR) of 2.99 (95%CI 1.52–5.88;  P  = 0.001). This association was confirmed in multivariable analysis (HR 2.22, 95%CI 1.12–4.44;  P  = 0.024). In addition, statistically significant associations were observed between the cell-in-cell structures and other adverse histopathologic characteristics including deep invasion ( P  <  0.001), high index of tumor budding ( P  = 0.007), worst pattern of invasion ( P  <  0.001), perineural invasion ( P  = 0.01), and stroma-rich pattern ( P  = 0.001).    Conclusions  Our findings demonstrate a significant relationship between cell-in-cell formation and aggressive characteristics of early OTSCC. Cell-in-cell structures have a distinct impact as a novel prognostic indicator in early OTSCC and they can be easily assessed during routine pathology practice.

Cell-in-cell phenomenon associates with aggressive characteristics and cancer-related mortality in early oral tongue cancer