HPV-Specific head and neck cancers The first evidence implicating HPV’s involvement in oral squamous cell carcinogenesis was published in 1983 (Syrjanen, Syrjanen, Lamberg, Pyrhonen, & Nuutinen, 1983). Research aimed at understanding the role of HPV in oropharyngeal cancer is relatively new and although evidence substantiates the presence of HPV type 16 in the oropharynx and oral cavity, its specific role in precancerous and cancerous oropharyngeal lesions has not been fully explained (Candotto, et al., 2017). Nevertheless, the mechanism by which high-risk viruses can transform epithelial cells into cancer has been thoroughly studied. Papillomaviruses infect basal keratinocytes and maintain their genetic material as an episome , or small bit of circular DNA located in the infected cell’s cytoplasm. It is here that the virus expresses two sets of genes: early (E) genes and late (L) genes. Early genes, specifically E6 and E7, induce normally growth-arrested, differentiating parabasal keratinocytes to maintain their DNA replicative machinery, which the virus then usurps for its own replication. Once replicated, the late genes that code for structural proteins are activated and orchestrate viral particle production. Mature virus is synthesized, assembled, and shed from the host in sloughed epithelial cells. Cell growth and DNA replication is tightly controlled in a normal cell and is a result of a balance between tumor suppressor proteins, which restrict replication of DNA and cell division, and proteins made by proto-oncogenes, which are genes that promote cell growth. Indeed, loss of tumor suppressor proteins or overactivity of proto-oncogenes through genetic damage and mutation is the first step in the development of a cancer. In HPV infection, E genes work by binding to and neutralizing tumor suppressor proteins so the virus can “trick” the cell into activating a program of DNA replication. The result is multiple copies of viral DNA but also inappropriate epithelial cell proliferation that manifests clinically as a wart. Unfortunately, in some high- risk HPV infections, the viral episome normally maintained in the cytoplasm can break apart and integrate into the host DNA in the cell’s nucleus, resulting in loss of control over the expression of E6 and E7. Uncontrolled co-expression of E6 and E7 leads to enhanced degradation of tumor suppressor proteins and, eventually, to cancer (Tumban, 2019). For example, one of the tumor suppressors neutralized by the HPV early protein E6 is called p53, a protein so important in restriction of cell growth and protection against cancer that it is known as the guardian of the genome . Mutations in p53 are common in numerous human malignancies, including oral cancers where mutations are induced by carcinogens found in tobacco. In HPV-induced oral cancer, however, p53 function is lost through E6-mediated degradation rather than DNA damage and mutation. Because the oropharynx is the head and neck site most vulnerable to the development of cancers attributed to prior HPV infection (van Heerden, et al., 2017; American Dental Association, 2019a; Candotto, et al., 2017). The National Cancer Institute (n.d.) recommends that all oropharyngeal tumors be tested for the presence of HPV. HPV’s preference for proliferation in the oropharynx is as yet unexplained. The mucosal lining of both the tonsils and tonsillar crypts within the oropharynx allows the direct passage of the cellular elements of the immune system and also pathogens such as the HPV (Taberna, et al., 2017). The anatomy of the tonsillar epithelium facilitates capture and survival of the HPV type 16 virus as it is similar to the squamous cell junction of the cervix (Candotto, et al., 2017).
Because the symptoms are not always obvious to the individual developing the disease, HPV-positive oropharyngeal cancers are harder to detect than the traditional tobacco/alcohol-related cancers (Stenson, n.d.). Compounding this problem is the primary location of cancer development, which is the oropharyngeal area, namely the base of the tongue, back of the throat, tonsils, tonsillar crypts, and tonsillar pillars (Oral Cancer Foundation, n.d.).These areas are sometimes difficult to clearly visualize during an oral examination. HPV-positive head and neck cancers differ from those that are HPV-negative (Ducatman, 2018), both in their clinical behavior and histopathological appearance when examined under the microscope. Conventional tobacco-related cancers form more anteriorly and favor sites such as the floor of the mouth and lateral tongue. Histopathologically, these tumors are usually well-differentiated keratinizing squamous cell carcinomas characterized by large polygonal squamous cells with distinct cell borders, intracellular bridging between neighboring cells, and keratin production that resembles normal epithelial cells of the upper spinous layer. Because of the relatively high level of differentiation, tobacco-related oral cancers usually do not exhibit features indicative of rapid growth, and therefore lack excessive numbers of mitotic figures and necrosis, or cell death resulting from growth that overcomes the ability of the tumor to acquire nutrients and oxygen. Clinically this results in slower growth than what is seen in HPV-induced oral cancers, which exhibit a less differentiated appearance more closely resembling the basal cell layer and are characterized by numerous cells undergoing mitosis, little to no keratin production, and comedo-type necrosis, or cell death occurring in the center of rapidly growing islands of tumor (Westra, et al., 2017). When compared to HPV-negative head and neck cancer, HPV-positive cancers are typically more responsive to therapy, and in general most patients have a better prognosis (Ducatman, 2018; NCI, n.d.; You, et al., 2019; Candotto, et al., 2017; Lassen et al., 2018). Individuals with HPV-positive oropharyngeal cancer have a disease- free survival rate of 85% to 90% over 5 years, compared to the traditional oropharyngeal cancer patients (associated with alcohol and tobacco use). With advanced disease, the HPV-negative cancers have a 25% to 40% 5-year survival rate (Mount Sinai Hospital, n.d.). The three-year survival rate for patients with HPV-negative oropharyngeal malignancies is 46.2 % while those with HPV-positive oropharyngeal malignancies had a 71% survival rate at three years (Candotto, et al., 2017). Among the factors contributing to the more positive prognosis are younger age of HPV-positive oropharyngeal cancer patients (Mount Sinai Hospital, n.d.), lack of genetic mutations in the DNA of infected cells (compared to the DNA damage occurring in epithelial mucosa from alcohol and tobacco), and the more rapid growth of HPV-associated cancers, which paradoxically makes them more responsive to chemo- and radiotherapy (DeFelice, et al., 2019).
EliteLearning.com/Dental
Page 111
Powered by FlippingBook