**4. Carcinogenic mechanisms associated with osseointegrated dental implants**

Titanium is one of the most common components in implants alloys used in dental and medical fields [1, 29]. High biocompatibility, appropriate mechanical properties, inertness, and corrosion resistance are among the main advantages of titanium [25, 29, 30]. When the titanium implant is installed in extra oral sites, where it is protected from the contact with the environment, it has inert behavior. On the other hand, dental implants are continuously exposed to the oral cavity hostile conditions [31]. The area between the implants and the abutment or the prosthetic crown is particularly susceptible to the bacterial biofilm accumulation, saliva, pH and temperature changes, and functional micromotion (**Figure 2**) [31].

When the dental implant surface is exposed to any source of oxygen or nitrogen, a chemical reaction takes place and a thin layer of titanium dioxide (TiO2) is formed and deposited in the outer surface of the implants. This layer is extremely resistant to corrosion. However the chemical agents of the oral cavity can reduce the protection of the dioxide deposit and induce the corrosion development [31]. Saliva and other chemicals introduced into the oral cavity through feeding or in contact with bacterial biofilms influence the gradual biodegradation of metallic structures including the titanium used in dental implants [29]. Furthermore, acidic solution combined with mechanical friction strength potentiates the damages to the implants surfaces. Interestingly, some studies with cytology have demonstrated the presence of titanium

#### **Figure 2.**

*Illustration of potential risk factors and mechanisms on the development of squamous cell carcinoma around dental implants.*

#### *Oral Cancer around Dental Implants: Are the Clinical Manifestations and the Oncogenic… DOI: http://dx.doi.org/10.5772/intechopen.101156*

particles in the peri-implant tissues [23, 25] regardless of the presence of peri-implantitis or peri-implant mucositis. It has been suggested that this material accumulation may be the result of the corrosive process of the dental implants [29, 30, 32], implantabutment friction at the installation of the implants, and/or implantoplasty [29, 31, 33, 34]. The degree of titanium corrosion can be influenced by quality and quantity of saliva, diet, alloy polishing, genetics, oral hygiene, amount and distribution of the occlusal forces, and microbiota [29, 30, 32].

The above data show that titanium is not entirely bioinert as suggested years ago. Then, even with their good biological properties, titanium alloys are susceptible to corrosion attack with release of metal ions to the surrounding hard and soft oral tissues, lymph nodes, peripheral, and even distant organs [30]. Consequently, titanium ions have been implicated in the development of oral cancer around dental implants [1, 34].

As stated previously, the relationship between titanium dental implants and oral cancer has been suggested based on the increasing number of tumors arising in the peri-implant tissue. However, as far as we know, there is not any study dedicated to unveil the potential carcinogenic mechanisms triggered by titanium ions.

Titanium particles have been shown to induce the expression of breast cancer gene 1 (BRCA1) and checkpoint kinase 2 (CHK2) in epithelial cells *in vitro* [35]*.* These proteins are markers of DNA damage response. Additionally, titanium also triggered the generation of reactive oxygen species (ROS) [36, 37]. The chronic exposure of the epithelial cells to aggressive factors may increase the probability of mutations that might not be detected by the immune system. Indeed, the chronic inflammatory response seems to be also modulated by titanium, especially when there is accumulation of bacterial biofilm. Higher amounts of titanium ions in peri-implant soft tissue with inflammatory process are observed when compared to healthy tissues [25, 38]. Accordingly, titanium nanoparticles induced stronger pro-inflammatory response in macrophages regardless of the association with lipopolysaccharide from *Porphyromonas gingivalis* [39] and by increasing the secretion of interleukin (IL)-6, IL-1β, and tumor necrosis factor-alpha (TNF-α) by macrophages *in vitro* [38, 40]. Taken together, all these disturbances in the peri-implant microenvinoment may persist for years and, gradually, predispose the epithelial cells to sequential mutations until the malignant state is reached.

In 2006, the International Agency for Research on Cancer (IARC) classified the titanium dioxide as a possible carcinogen for humans [41]. However, in view of the few case reports of oral cancer around dental implants the authors were unable to exclude the existence of other confounding carcinogens as tobacco and/or alcohol [1, 7, 19].

### **5. Conclusion**

The literature review showed that most cases of OSCC around dental implants had initial clinical features compatible with peri-implantitis. Therefore, this clinical misinterpretation of an inflammatory process in peri-implant mucosa may delay the diagnosis of oral cancer facilitating the local progression and dissemination of cancer cells, resulting in worst patient's prognosis. Thus, the peri-implant lesion not responding to conventional anti-inflammatory treatment, particularly if the patient has risk factor for oral cancer, should be submitted to the biopsy and histopathological analysis, avoiding delay in the diagnosis of the tumor.
