Significance of the fibrous stroma in bone invasion by human gingival squamous cell carcinomas

Gingival squamous cell carcinomas (SCCs) frequently invade the mandible or maxilla, and this invasion is associated with a worse prognosis. Although previous studies have suggested that bone destruction caused by gingival SCC is mediated by osteoclastic bone resorption rather than by tumor cells directly, the mechanism underlying the bone invasion remains poorly understood. We histopathologically investigated mandibular invasion patterns in 97 cases of primary gingival SCC and evaluated the correlations between bone invasion patterns and clinicopathological factors. Based on the histological examination of the mandibular invasion pattern, we classified the cases into 2 categories: expansive type and infiltrative type. Of the 97 cases, 52 were expansive type and 45, infiltrative type. Varying numbers of Howship's lacunae and osteoclasts were detected on the bone surface adjacent to the tumor cells. Compared to the expansive type, the infiltrative type showed increased numbers of osteoclasts at the interface of the tumor and the resorbing bone. Tumor cells showed no direct contact with osteoclasts and the adjacent bones, and in all cases varying amounts of fibrous connective tissues intervened between the tumor cells and the bone. The number of fibroblasts was significantly greater in the infiltrative type than in the expansive type. We also found a positive correlation between the number of osteoclasts and fibroblasts at the interface of the tumor and the resorbing bone. Immunohistochemistry revealed RANKL expression in the fibroblastic cells that were adjacent to the osteoclasts in the area of bone resorption. In coculture experiments, human gingival SCC cells (BHY) stimulated the expression of mouse RANKL mRNA in murine osteoblastic cells (MC3T3-E1). These results indicate that the fibrous stroma plays critical roles in osteoclastic bone resorption by gingival SCC through the RANKL-dependent pathways.