Microarquitetura cortical e expressão gênica de RANK, RANKL, OPG e SOST na mandíbula: influência na sobrevida global de pacientes com carcinoma epidermóide oral submetidos à mandibulectomia

Abstract

Oral squamous cell carcinoma (OSCC) is a malignant neoplasm that comprises about 90% of malign lesions of the oral cavity. Lesion interaction with microenvironment occurs through several molecular mechanisms, including the crosstalk between bone and tumor. Regarding the bone, metabolism-related genes expression, including RANK/RANKL/OPG and SOST, is probably altered. Bone involvement and invasion are related to the prognosis and survival rates. In this way, the aim of this study was to evaluate the expression of genes involved bone remodeling process in the mandible of patients diagnosed with OSCC, together with the evaluation of microarchitectural parameters in the cortex, and their influence on prognosis. Twenty-four patients who underwent mandibulectomy were included in the study, and two bone fragments were collected from the surgical specimen: one for gene expression analysis by means of quantitative real-time PCR (qPCR), and the other that was included in methyl methacrylate for Microtomography evaluation (µCT, 19 µm isotropic voxel, Scanco MicroCT40, 55 kVp, 144 μA). The following cortical parameters were evaluated: bone volume (BV, %), bone surface (BS, µm), porosity (Po, %), number of pores (NP, n), bone mineral density (BMD, g/ cm³ HA) and fractal dimension (FD, #). A Kaplan-Meier estimator was used to assess survival, and simple Cox regression was applied to quantitative variables. There was a predominance of male patients (70.8%) and the mean age was 59.71 years (median of 62 years). Moderately differentiated tumors were diagnosed in 75% of cases. The bone invasion was identified in 33.3% of the cases. RANK, RANKL, and SOST genes were mostly downregulated (cases with bone invasion: 25 situations of downregulation and 3 of normal expression; cases without invasion were 38 situations in downregulation and 6 in normality), while OPG presented 100% of downregulation. There were no cases of overexpression. Regarding microarchitectural parameters, the mean Po was 3.28% (±4.18), NP was 39, BMD was 1.07 g/cm³ HA, and FD was 1.20. Overall survival analysis revealed that the variables age (p 0.01) and tumor size (p 0.01) were statistically significant. There is a higher risk of death for patients younger than 56 years of age (11.3 times greater risk) and for tumors larger than 6 cm (7.5 times greater risk). In conclusion, there is a predominant gene downregulation in the mandibular bone, suggesting a partial bone metabolic inertia in the proximity of the OSCC lesion. Gene expression was not influential on overall survival. Osteoprotegerin was downregulated in 100% of the cases. Overall survival rates of OSCC patients submitted to mandibulectomy were negatively influenced for individuals under 56 years of age and for tumors larger than 6 cm.