# The Link between Periodontal Disease and Oral Cancer--A Certainty or a Never-Ending Dilemma?
## 4 Periodontal Disease and Oral Cancer  
### Oral Cancer  
Five percent of all malignancies are head and neck cancers, with half of them occurring in the oral cavity [74]. Oral cancer is a type of malignant neoplasia that develops on the lips or in the mouth. Squamous cell cancer is the standard definition. Despite all the advanced techniques that have emerged in recent years, such as adjuvant radiotherapy and chemotherapy, the global prevalence of squamous cell cancer appears to be growing and the overall survival rate for 5 years remains low--between 50-60% [75].  
Oral cancer is a major public health issue that can affect anyone. It is among the top ten cancers in terms of incidence, and despite advances in research and therapy, survival has remained stagnant in recent years, posing a constant challenge for biomedical science.  
Oral cancer is two to three times more prevalent in men than women. In worldwide reports, cancers of all regions of the oral cavity and pharynx are grouped and collectively represent as the sixth most common cancer in the world [76]. Oral cancer is a preventable disease in which significant risk factors such as smoking and drinking are present in 90% of cases [77], resulting in a synergistic impact [78].  
According to the International Agency for Research on Cancer's recent studies on oral cancer, which affects the lips, tongue, gingiva, mouth floor, and salivary glands, has increased with over 300,000 cases diagnosed and 145,000 deaths per year.  
Oral carcinogenesis is a multifactorial, complex process that happens when epithelial cells are influenced by multiple genetic changes. Although cancer has been known for a long time, it is only in recent years that the mechanisms of cancer onset and evolution have begun to be figured out in more depth. As early as 150 years ago, [PERSON], the founder of cellular pathology, showed that cellular hyperplasia occurs in cancer, and is characterized by an abnormally large increase in the number of cells whose division has spiraled out of control [79]. Oral carcinogenesis is thought to begin with the transformation of a small number of normal keratinocytes.  
Changes in cytogenetics and epigenetic mechanisms can also contribute to this transition. These changes can affect the cell cycle, DNA repair processes, and cell differentiation. Risk factors can be added to these changes, resulting in an unstable keratinocyte, which eventually transforms into a pre-cancerization field--causing malignant neoplastic alterations [80].  
Overexpression of cytokines, produced by oral squamous cell cancer (OSCC), suppresses the adaptive immune response via T-cell mediated apoptosis and changes in the antigen processing machinery [81].  
Oral cancer begins with non-aberrant keratinocytes exposed to a stimulus that disrupts their homeostasis over time, leading to epithelial hyperplasia, dysplasia in different degrees, carcinoma in situ, and the last stage, an invasive carcinoma. According to statistics, the tongue (ventral-lateral edge, 40% of cases), the floor of the mouth (30% of cases), and the lower lip are the most prevalent sites for oral cancer presentation [82].  
Diagnostic markers have recently been the subject of clinical and experimental research. A diagnostic cancer marker can be specific to the stage, tissue, relapse, follow-up, or age, and it can appear at any point during the progression of cancer. Despite attempts to define cancer biomarkers, there has yet to be a consensus. Among the laboratory tests available, liquid biopsy is a less invasive approach that eliminates the need for tissue collection. Blood is currently the most common liquid biopsy. For a liquid biopsy, approximately 5 to 10 mL of blood is required. However, more recent research has focused on innovative and noninvasive technologies involving human saliva sampling, such as proteomic analysis, for diagnosing and understanding the OSCC genetic architecture [83].