How pathological criteria can impact prognosis of tongue and floor of the mouth squamous cell carcinoma

Abstract Pathological parameters have been indicated as tumor prognostic factors in oral carcinoma. Objective: The objective of this study was to investigate the impact of pathological parameters on prognosis of patients affected only by tongue and/or floor of the mouth squamous cell carcinoma (SCC). Methodology: In total, 380 patients treated in the Brazilian National Cancer Institute (INCA) from 1999 to 2006 were included. These patients underwent radical resection followed by neck dissection. The clinical and pathological characteristics were recorded. The Kaplan-Meier method and Cox proportional hazards model were used in survival analysis. Overall survival (OS), cancer-specific survival (CSS) and disease-free interval (DFI) were estimated. Cox residuals were evaluated using the R software version 3.5.2. Worst OS, CSS and DFI were observed in patients with tumors in advanced pathological stages (p<0.001), with the presence of perineural invasion (p<0.001) and vascular invasion (p=0.005). Results: Advanced pathological stage and the presence of a poorly differentiated tumor were independent prognostic factors for OS and CSS. However, advanced pathological stage and perineural invasion were independent predictors of a shorter OS, DFI and CSS. Conclusion: Pathological stage and perineural invasion were the most significant pathological variables in survival analysis in tongue and/or floor of the mouth SCC.


Introduction
Head and neck cancer is the sixth most common type of cancer, 1 being strongly associated with tobacco and alcohol consumption. Several regions, including the oral cavity, can be affected by these tumors. Squamous cell carcinomas (SCC) are the most common type of tumor in this region. Oral cancer is usually caused by epithelial lining cell transformation.
The incidence of 354,864 new cases for both sexes was expected worldwide in 2018. 1 When compared to other South American countries, Brazil presented the highest rates of oral cancer. 2 Data from the Brazilian National Cancer Institute (INCA) estimated that oral cancer was the fifth most common type of cancer among men and the 12 th among women in 2018. 3 Tongue is the most commonly affected site in oral cavity, followed by the floor of the mouth. 4 Studies show that tumors on this site have a worse prognosis than other sites in the oral cavity due to their incomplete response to treatment strategies, resulting in lower survival rates. 5 Consequently, cancer of the oral cavity has higher mortality rates (50%) when compared to other types of cancer. 1 The TNM classification is used clinically to define therapy and estimate its response and prognosis. 6 However, it does not necessarily reflect a precise

Data collection
All medical records and pathologic reports were reviewed and the data were collected as shown in Table   1. Pathological data included tumor stage (pTNM).

Results
All the 380 patients of a single institution received the same protocol procedures for diagnosis and treatment. Tumor-derived specimens had the same histological type (squamous cell carcinoma) and site (tongue and floor of the mouth). The profile of the studied population followed REMARK's recommendations. 14 Figure 1A
We were unable to assess the depth of invasion in our study due to only using medical records. Also, this study was carried out before the publication of the new edition of the TNM Classification of Malignant Tumours. 12 Therefore, we are planning to include these new parameters in the studied population.

Overall survival
Cancer-specific survival Disease-free interval   Moreover, we selected, according to our inclusion criteria, patients considered free surgical margins.
Positive margins can significantly decrease overall survival and increase the risk of local recurrence. 9,26 Furthermore, our data suggest that pathological TNM staging is an important prognostic factor due to its ability to predict not only OS and CSS, but also DFI.
In addition, this variable predicts both OS and CSS independently. Amit, et al. 27 (2018) showed the same results, with a significant association with OS and CSS in multivariate analysis for pathological TNM stage.
Our study confirms that perineural invasion is a predictor of unfavorable DFI, which was already observed in a previous study with the same criteria. 24 Perineural invasion was also a predictor of worst OS and CSS and showed an independent prognostic value in multivariate analysis. Vascular invasion has been significantly associated with survival 11 , but our study also showed it as a significant prognostic indicator for OS, CSS and DFI.
Also, our data showed poor differentiated tumors as an independent predictor for CSS. As limitations of this study we point the use of secondary sources, such as histopathological reports and medical records, and the unavailability of some information. Histopathological reports were performed by different pathologists from the same institution. We suggest an additional study including tumors in other sites to complement our observations. However, our findings reinforce the need to describe all pathologic parameters in histopathological reports.

Conclusion
In conclusion, pathological criteria have direct impact in patient's prognosis. In addition, an independent predictor of survival was found for pTNM, perineural invasion and WHO grading system. Our study highlights the fact that the WHO grading system is also a promising prognostic indicator for tongue and floor of the mouth SCC.

Conflict of interest disclosures
The authors declare no conflicts of interest.