Influência do perfil inflamatório celular no microambiente tumoral no prognóstico e meta-análise da sensibilidade imunohistoquímica na detecção de invasão perineural e angiolinfática em carcinoma de células escamosas oral

Abstract

The prognosis of oral squamous cell carcinoma (OSCC) is related to staging and the tumor microenvironment (TMA), which is highly heterogeneous, complex, and composed of different cell types. This work has two chapters, comprising a systematic review with meta-analysis and a retrospective study. The aim is to understand the influence of the cellular profile of the tumor microenvironment on the prognosis of OSCC. In Chapter 1, a systematic review and meta-analysis (PROSPERO - CRD 42021256515) was performed to analyze whether immunohistochemistry is more sensitive than hematoxylin-eosin staining for identifying perineural or angiolymphatic invasion in OSCC. Data were obtained from six databases (PubMed, Scopus, LILACS, Web of Science, EBSCO, LIVIVO, Embase) and grey literature. The meta-analysis (random effect) was calculated using MedCalc 18.2.1 software (MedCalc®) (p<0.05). Four observational studies were included, totaling 560 patients with 295 biopsies reviewed for pathologies and analyzed by immunohistochemistry. The combined sensitivity was 76%, since the samples evaluated by Hematoxylin-Eosin (HE), which detected perineural invasion (PNI) and lymphovascular invasion (LVI), were also identified by the immunohistochemical method. The specificity of the four included studies revealed that, using HE, 42% of squamous cell carcinomas (SCCCs) did not show PNI and LVI, which was confirmed by performing the immunohistochemical technique. Therefore, the use of immunohistochemical reactions to highlight tumor invasion in nerves and blood or lymphatic vessels is effective in cases where H&E analysis resulted in a negative result, thus decreasing the prevalence of false negative cases. Chapter 2 aimed to characterize the immunoexpression of macrophage and lymphocytic phenotypes in oral squamous cell carcinoma, correlating it with prognostic factors and cell proliferation markers. To this end, 228 oral squamous cell carcinoma (OSCC) samples from the Ceará Cancer Institute (ICC) were evaluated. Sociodemographic and clinicopathological data were collected, and immunohistochemistry was performed for anti-CD3, CD4, CD8, CD20, and CD68 markers in peritumoral and intratumoral regions. However, Ki67 was only found in the intratumoral area. The percentage of immunostaining was calculated and associated with other variables using the Friedman/Dunn and Wilcoxon tests. The most frequent lymphocyte profile was CD3 positive in the peritumoral region (p<0.001). Furthermore, Ki-67 expression >5% was associated with high intratumoral CD4 expression (p=0.018). It was observed that patients with lymphovascular invasion presented high expression of peritumoral CD8 (p=0.034) and CD20 (p=0.034). Tumor sprouting was significantly related to low expression of CD68 in the peritumoral region (p=0.035). Multivariate analysis demonstrated that peritumoral CD20 is inversely related to recurrence-free survival at 18 months, reducing the risk of recurrence at 18 months by 0.291 times, while intratumoral CD68 is directly related, increasing the risk of recurrence at 18 months by 5.07 times. Furthermore, lymphovascular invasion (p=0.001) and nodal metastasis (p=0.009) significantly increased the risk of recurrence at 18 months in patients with oral squamous cell carcinoma. The participation of BCD20+ lymphocytes in the tumor microenvironment may provide antitumor behavior, since the loss of expression of these cells led to an increased risk of recurrence of oral squamous cell carcinoma. Furthermore, increased CD68+ expression was shown to increase the risk of oral cancer recurrence. Therefore, lymphovascular invasion and nodal metastasis proved to be independent predictors of recurrence.