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Introduction to Oral Cancer Genetics
Oral cancer can develop in any part of the oral cavity or oral pharynx (Figure 1), but the most common sites are the floor of the mouth, lips, soft palate, and tongue. Mouth cancer is considered anything from the last molar forward to the lips, including the part of the tongue seen in the mirror, the hard palate and the inside of the cheeks. Anything behind the last molar is a different area, called the oropharynx, which includes the tonsils, soft palate and the base of the tongue. Cancers of the hard palate are not common in the United States. The most recent estimates in 2013 from the American Cancer Society show that each year over 36,000 people will be diagnosed with oral or oropharyngeal cancer and over 6,850 people will die from these cancers.
Oral cancer is more common than cancers of the brain, liver, bone, stomach, cervix, and ovaries; it is even more common than leukemia. When oral cancer is detected early, the cure rate can be as high as 96% depending on the location of the cancer. Unfortunately, by the time a medical or dental diagnosis is made, about two-thirds of oral cancers are advanced lesions with evidence of invasion and metastasis. This leads to high morbidity and mortality in spite of advances in surgical techniques, radiotherapy and chemotherapy. Little has changed in the last 40 years and approximately half of the people who develop oral cancer die because of the disease. Oral cancer is particularly dangerous because it has a high chance of producing secondary tumors, usually in the lymph nodes of the neck. This increased risk factor can last up to a decade after the first episode of tumor invasion.
Annually, oral cancer kills more people than female cervical cancer and costs society more than $2 billion in treatment costs and lost wages. Many of these malignant conditions could be arrested if detected earlier. The dental profession has a unique opportunity during patient assessment to detect oral cancer while it is still asymptomatic, innocuous, and unsuspected. It is estimated that 5-10% of routine dental patients have some unusual findings, from something as harmless as mandibular or maxillary tori to something as serious as a malignant neoplasm. Oral squamous cell carcinoma accounts for 90% of all primary oral malignancies. It is possible for the oral cavity to be the site for tumor metastasis from other locations, such as the breast, lung, and gastrointestinal tract.
Cancer of the three major salivary glands (parotid, submaxillary, and sublingual) is considered a separate form of oral cancer, as are cancers of the jaw and the muscles of the face. Therefore, it is important to identify the area the cancer originated from, even if it has spread to other areas of the head. The origin is the factor that determines the type of cancer.
Oral cancer affects men twice as often as women. It is more common among African-Americans than Caucasians, and seen more often in those of lower socioeconomic status. The average age at onset is 62 years old. Most patients are over 40 years old, but it is also important to remember that oral cancer can strike at any time. The exact causes for those affected at a younger age are not known at this time. There are some probable links to young males who use chewing tobacco. Other researchers believe that the underlying link is viral based, given that the amount of time these individuals have been exposed to known causative agents, such as tobacco, is short.
From a gender perspective, oral cancer had affected six males for every female for decades. The ratio is now two males for every one female. Published studies do not draw concrete conclusions as to why females have closed the gap, but many believe that lifestyle changes in which the number of women smokers has increased over the last twenty years plays a significant role.
From a racial and an ethnic perspective, oral cancer occurs twice as frequently in the African American population as it does in the Caucasian population. Among African American men, the oral cavity is the fourth most frequent site of cancer. Survival statistics for an African American individual over a five-year period are about 40%, while for a Caucasian individual it is approximately 60%. Researchers are unlikely to find a genetic reason for this anytime soon. Published statistics do not take into consideration socio-economic factors such as availability of proper health and dental care, education, income levels, and the increased use of both tobacco and alcohol by different ethnic populations.
Age is frequently named as a risk factor for oral cancer since most cases occur in those over the age of 40. The average age of those diagnosed with oral cancer is 62. The ages of the diagnosed patients may indicate a time component in the biochemical or biophysical processes of aging cells that allows malignant transformation. New trends inevitably emerge, and recently there has been an increase in the number of patients in their 20's and 30's who have developed oral cancer, especially cancer of the tongue, without any apparent risk factors such as tobacco and alcohol use or immunosuppression.
Oral cancer is a multi-step process of accumulated genetic mutations caused by a combination of diet, alcohol and tobacco use, oral hygiene, lifestyle, lowered immunity, and genetic susceptibility. The use of tobacco in all of its forms (cigarettes, cigars, pipes, marijuana, and chewing tobacco) is a well-established risk factor for not only oral cancer, but other cancers as well. In oral cancer, it is considered the number one risk factor. Even children who use chewing tobacco, often to emulate famous baseball players, have developed oral cancer. A strong association has been noted between development of oral premalignancy in the form of erythroplakias and the use of chewing tobacco combined with alcohol consumption. Pipe smokers have a greater incidence of developing lip cancer. The more tobacco that is used for a longer period of time, the higher the risk for oral cancer. Likewise, when tobacco usage is stopped, the risk declines to almost normal over a 10-20 year period.
Excessive alcohol use can also increase the risk of developing oral cancer. One theory suggests that alcohol generates metabolites that are carcinogenic to humans; the major metabolite of ethanol is acetaldehyde, a known carcinogen. Acetaldehyde may be produced both systemically and by the oral microflora. Alcohol may also act as a solvent for tobacco, making it easier for the carcinogens to infiltrate the oral mucosa. The use of both alcohol and tobacco simultaneously generates a greater risk for oral cancer than using either substance alone. It is estimated that the combination of both smoking and drinking causes approximately 75% of all oral and pharyngeal cancers in the United States. As with tobacco, lowering the frequency of alcohol usage gradually lowers the risk of cancer to that of non-drinkers who don't smoke.
Research suggests that diets lacking fruit and vegetables could contribute to oral cancer, as well as other forms of cancer. Fruits and vegetables contain beneficial antioxidants that trap harmful molecules called free radicals. Antioxidants can help prevent cancer causing genetic mutations. Natural carotenoid compounds, dietary selenium, folate, and vitamins A, C, & E reportedly offer protection against cancer development. Consumption of Cantonese salted fish from early childhood on into adulthood has been associated with oral cancer formation in some Asian countries. Betel nut chewing in Indian populations is strongly associated with tooth loss and oral cancer, due to prolonged irritation of the tissues.
Each teaspoon of saliva contains about 1 billion bacteria, which are making waste products that cling to the teeth in the form of plaque. This sticky white film can easily be removed with proper daily brushing and flossing techniques. If plaque isn't removed, it will calcify over time and cause irritation to the teeth and gums. Plaque itself is not shown to cause oral cancer, but it aids other irritants like tobacco and alcohol to stick in the mouth, irritate the tissues, and stimulate the cells to divide. The more cells that divide, the greater chance one of them will become cancerous. The common thread of many risk factors is irritation, which can lead to a lot of cell division. Poor fitting dental appliances such as partials and dentures irritate the gingiva and trap debris. Continued irritation can lead to lesions and eventually develop into oral cancer (Figure 2).
The decision to smoke or drink is certainly a lifestyle risk factor. Those who do not smoke or drink alcohol have a lower risk of developing oral cancer than those who choose to indulge. Ultraviolet radiation is another lifestyle risk. Cancer of the lip is one oral cancer that has declined over the past few decades, most likely due to society's increased awareness of the damaging effects of prolonged exposure to sunlight and the increased use of sunscreen products.
Infections such as syphilis can lead to cancer over time due to poor healing mouth sores that are repeatedly irritated. The constant attempt to heal affected tissue leads to chronic cell division and a greater chance for cancer to develop. Lowered immunity from AIDS or transplant anti-rejection drugs will increase the risk for many cancers, including those of the aero-digestive tract (the area from the nose and mouth to the lungs and stomach).
Some viruses are suspected in the development of oral cancer. Viruses can get into the cells of the oral cavity and change the genes in them to form a cancer cell. This process is known as "oncogene activation." The Human Papilloma Virus (HPV), particularly the HPV-16 and the HPV-18 strains, and the Herpes Viruses are now considered contributors to some oral cancers. The HPV-16 and the HPV-18 strains are the causative agents in cervical cancer, accounting for 70% of all cervical cancers. DNA from HPV and particular herpes viruses (including the Epstein-Barr, cytomegalovirus, and herpes simplex) has been discovered in biopsies from the oral cavity. Each year, more than 2,370 women and 9,350 men are diagnosed with HPV associated oropharyngeal cancer. Studies have shown a dramatic increase of 225% when looking at cases of HPV associated oropharyngeal cancer from 1988 to 2004. As with many other types of oral cancer, oropharyngeal cancer is 2 times more likely in men than women. Genes encoded within these viruses are involved in the initiation of the multiple steps needed for a normal cell to become malignant. Two genes, Rb and p53 regulate normal cell division. Rb has the role of separating transcription factors needed for progression through the cell cycle, preventing the normal cells from dividing until it has separated enough transcription factors. Rb is a tumor suppressor gene that segregates a protein called E2F. When normal cells are infected with HPV, the E7 gene from HPV binds to Rb, releasing E2F and other proteins, signaling the start of the cell cycle. This cycle continues as long as E7 remains attached to Rb. Uncontrolled cell division is a sign of malignancy.
The other gene that HPV attacks is the p53 gene, responsible for repair of damaged DNA and apoptosis in the event that repair is impossible. In malignant cells, p53 is often nonfunctional or missing entirely. The viral E6 protein binds to p53 making it nonfunctional. Damaged DNA is then replicated continually since the non-functional or missing p53 does not initiate apoptosis. E6 protein also activates telomerase, an enzyme that synthesizes the telomere repeat sequences. The activation of this enzyme ensures the repeated cell cycle that continually produces more viral cells, leading to malignancy.
Scientists have linked a new virus (human herpes virus-8) with AIDS-related Kaposi's Sarcoma, another cancer that prefers the head and neck region. Oral lesions are present in about half of the Kaposi's Sarcoma cases, with the hard palate and the gingival areas being the most commonly affected areas. This new virus has been found in all forms of Kaposi's Sarcoma, insinuating that it might be involved in sarcoma development. A direct role has not yet been identified.
Signs and Symptoms
One of the greatest dangers of oral cancers, especially in the early stages, is that it can go unnoticed. Unfortunately, and all too often, the earliest symptoms are noticed when body function is affected. Early oral cancer symptoms can be painless, hidden, and not bothersome. Oral precancer and cancer exhibit a wide range of clinically detectable alterations that may range from an early, subtle change in surface texture, color, or elasticity to a more obvious lesion. Changes in the oral epithelial cells often present as white, or red/white patches called leukoplakia (Figure 3) or as velvety, red patches called erythroplakia (Figure 4). These changes represent cellular alterations that result from genomic changes within the surface epithelial cell population, including changes in DNA content, loss of heterozygosity, and genetic alterations in a cascade fashion that lead to the formation of invasive squamous cell carcinoma (Figure 5 and Figure 6).
The most common intraoral sites for squamous cell cancer are the lateral borders and ventral surfaces of the tongue, floor of the mouth, and the oropharynx. Any of the signs and symptoms that persist for longer than two weeks after removal of potentially irritating factors and/or application of therapeutic measures should be considered a cancer until proven benign by biopsy and microscopic evaluation.
Other cancers found less frequently in the oral cavity include carcinomas of salivary gland origin, lymphomas, melanoma, and bone and soft tissue sarcomas. Cancers that begin in other parts of the body may metastasize to or exhibit manifestations in the oral cavity. The most common metastases are from tumors in the lung, breast, colon, and kidney. Manifestations of leukemia, lymphomas, and multiple myeloma may also be present within the oral cavity.
(Common signs of oral cancer are listed in Table 1.)
The diagnostic phase of patient management begins with an assessment of the medical history and the possible impact and overall management of any oral disease or condition. Many times patients are not even aware they have a lesion or lump in the oral cavity, especially if it is hidden beneath the tongue. These deviations are often discovered during a routine head and neck examination, whether the patient is in for their recare visit or for some restorative work. The American Dental Association stresses the importance of doing routine head and neck exams and oral cancer evaluations on each and every patient. The screening takes just 90 seconds and can make the difference between life and death for the individual. Although there is no definitive set of steps for an oral cancer screening, there are several areas that should be routinely checked. Dental practitioners would be wise to check the following areas: sides and underside of the tongue, lips and cheek, floor of the mouth, palate, tonsils, and finally the neck.
Unfortunately, in the recent past, the number of oral cancers diagnosed at an early stage had not increased, possibly reflecting the lack of effective professional and public education. This trend is beginning to improve as more practitioners are doing regular screenings and diagnostic aids are improving. Early detection reduces morbidity and decreases mortality (Figure 7).
Ideally, a pathologist must test any observed suspicious mucosal abnormality obtained by using a scalpel, punch biopsy, or brush biopsy for evaluation. One essential tool for painlessly obtaining a full thickness sample of oral epithelium is the OralCDx® Brush (Figure 8 a and b). The OralCDx® is a brush biopsy followed by lab analysis in which a pathologist is aided by an advanced proprietary computer system. The suspected lesion is brushed with the special OralCDx® brush; collecting a sample from all cell layers down to the basement membrane. It is then smeared over a glass microscope slide and fixed. The brush is then placed in a vial. The slide and the vial are then sent to a laboratory where morphological and molecular biology tests are performed on the specimens. Results from the lab are usually available within 5 days. Should positive results be returned through this system, the brush biopsy must be followed by a conventional biopsy procedure. Scalpel and punch biopsies are used for highly suspicious lesions, whereas the OralCDx® is used for areas of color change that appear harmless but no clear clinical cause could be determined. Recent research has shown that brush biopsies such as OralCDx® can result in a high number of false positive results. One researcher reports that of 152 positive results from a brush biopsy there were only 12 cases that were truly dysplastic. Scalpel and punch biopsies are used for highly suspicious lesions, whereas the OralCDx® is used for lesions of uncertainty. Stage 1 oral cancers mimic many benign conditions seen more frequently. This is when the OralCDx® is best used.
Chemoluminescent lights are also available under the name of ViziLite® and VELscope®. VELscope® (Figure 9 and Figure 10) will fluoresce differently when normal tissues and the suspected tissue is exposed to certain wavelengths of light. Precancerous tissues become "excited" under exposure to this wavelength. ViziLite® first involves washing the mouth with acetic acid followed by using blue phenothiazine dye to mark the lesions. The wavelength of the illumination is absorbed by normal tissues and reflected back by abnormal tissues, making them easier to identify.
Toulidine blue, a selective binding stain on malignant cells, is a useful supplement to a clinical examination and biopsy. Use of this stain is economical, simplistic, and non-invasive with accurate results. Additionally, the use of this stain can assist in determining the most appropriate biopsy sites and to surgically delineate margins or malignant areas. One of the disadvantages of using this stain includes the risk of obtaining false negative reactions and the patient is not followed up adequately, resulting in a tissue biopsy.
Cells of the mouth divide quickly during development in the womb and throughout infancy. This rapid division slows down greatly as an individual ages so that it is just sufficient to replace cells that are dead or injured. The division of cells in the mouth and elsewhere is under very tight control, regulated by genes in the cells. When this control is lost, the cells begin to divide in a haphazard way, and grow to form a swelling of abnormal cells--a tumor. A benign tumor grows only within its local area, not spreading to distant organs. It is not cancer. A malignant tumor can spread to another area of the body and it is a cancer. Cancers of the mouth tend to grow to large sizes locally before they metastasize, but any cancer can spread at any time.
Scientists now understand that multiple mutations in specific classes of genes contribute to cancer of the head and neck. The two classes most fully characterized to date are proto-oncogenes and tumor suppressor genes. Proto-oncogenes code proteins that stimulate cell division. Altered forms of these genes called oncogenes can cause stimulatory proteins to be overactive, resulting in a cell dividing more rapidly than normal.
The oncogenes identified thus far as possible participants in oral cancer are shown in Table 2.
Tumor Suppressor Cells
Tumor suppressor genes code proteins that inhibit cell division. When these genes mutate, the corresponding protein is no longer produced correctly (in form, amount, or at time needed) and cell division may occur when it should not. Inactivated tumor suppressor genes that are suspected in oral cancer include Rb, p16 (MTS1 or CDKN2), E-cadherin, doc-1 and p53. E-cadherin is responsible for cell-cell adhesion and differentiation while doc-1 is induced by TNF-α and results in the inhibition of apoptosis and is deleted in oral cancer. P53 is already involved in approximately 60% of all human cancers.
There has been much interest in p53 since it was discovered that the gene can stop tumor formation when functioning properly. p53 is located on the short arm of chromosome 17. It works by recognizing damage to a cell's DNA and preventing continued cell growth and di- vision until the damage is repaired. If unable to repair, p53 causes the cell to experience apoptosis. p53 is also the gatekeeper of genome transcription and regulator of the angiogenesis inhibitor thrombospondin-1.
Appendix A (Table 3) lists the oral cancer genes and unique genes found in the Cancer Genome Anatomy Project so far. Appendix B (Table 4) lists the genes involved in oral cancer genetics that have been reported in literature to be up-regulated. Oral cancer results in many chromosomal changes. Chromosomal changes include recurrent chromosomal loss of 9, 13, 18, and 4; chromosomal deletions of 3p, 7q, 8p, 11q, and 17p; and chromosomal breakpoints in the centromeric regions of 1, 3, 14, and 15 on bands 1p22, 11q13, and 19p13. With ongoing research, more will be learned about the genetics of oral cancers.
The stages of oral cancer development are similar to the stages of many other cancers (Table 5 and Table 6). Once an actual diagnosis has been made, the degree of development and invasiveness is also determined. This determination aids in the treatment planning and prognosis for the patient. Although it is true that individuals who are diagnosed with cancer in advanced stages have a poorer prognosis of both cure and survival; it does not automatically mean that these individuals will have a poorer outcome.
Although the spread of oral cancer to regional neck lymph nodes is common and indicates an advanced tumor, metastases to other organ systems below the clavicle are rare. If a tumor should metastasize below the clavicle, the lung is the most common site. Metastases from oral cancers occur primarily through the lymphatic system, while distant metastases are hematogenous. The ability of malignant cells to metastasize varies among patients and depends on certain cell surface molecules and extracellular matrix interactions.
In order for a tumor to metastasize, the malignant cells must first break free from adjacent cells and the extracellular matrix. Cells are normally held close together with cell-cell adhesion molecules, allowing for interactions between the proteins on the cell surface. Cadherins, a type of adhesion cell molecule, is found to be partly or entirely missing in malignant cells. Without these molecules, the tumor is free to detach and travel to another site. Research has shown that saliva provides a good environment for metastasis. Hyaluronic acid, a molecule that binds to surfaces of the cell, is found in abundance in saliva and makes it easier for cells to move around, aiding in the escape from cell adhesion.
Another type of molecule called an integrin is needed to anchor the normal cell to the extracellular matrix. Without being anchored, a normal cell cannot reproduce and will eventually die. A nuclear protein called E-CDK2 regulates the cell cycle. Cancer cells do not need to be anchored to the extracellular matrix in order to reproduce. The cell cycle regulator E-CDK2 remains active and allows for continued proliferation. The exact reason for this integrin remaining active in malignant cells is uncertain, although researchers feel that oncogenes may be a key factor. Once a cancer cell has detached from both its neighbors and the extracellular matrix, it must find a way into the blood or lymphatic system for transport. In order to enter the bloodstream, the malignant cell must penetrate the basement membrane of the epithelial cells by releasing enzymes called metalloproteinases, which dissolve the basement membranes and extracellular matrices. Only certain cells of the malignant tumor are able to metastasize, and not all cancer cells have metastatic properties.
Treatment for oral cancer is different than other cancers. It is critical to get prompt diagnosis and proper treatment for a mouth cancer condition. It can mean the difference between life and death. The choice for cancer treatment is dependent upon the type and the stage of cancer. It may include surgery, chemotherapy, radiation, hormones, and/or immunotherapy. Some cancers respond to a single mode of treatment, whereas others require multi-modality treatment strategies.
The ultimate goal of the treatment is to remove totally or destroy the malignant cells from the body. Unfortunately, treatments available today are not able to target only the cancer cells, and normal healthy cells must sometimes be destroyed in the process of treating the cancer. This can result in significant psychological stress and physical morbidity or death. The goals of multi-disciplinary care are to cure the disease and prevent and assuage the side effects of treatment. Treatment does not stop at ridding the individual of cancer, but goes on to include the management of side effects of the treatment, and plan for reconstruction and rehabilitation. The dental profession plays a major role in the management of oral complications associated with cancer therapy and the prevention in some of the systemic problems that may occur.
Choice of treatment for oral cancer is dependent on the stage of the disease at the time of diagnosis. A small lesion of less than 1 cm may only require surgery or radiation therapy. Larger cancers, especially those that have spread to the lymph nodes in the neck, generally require surgery and radiation. Chemotherapy is not a curative treatment for oral squamous cell cancer, but it may be used as an adjunct before surgery or radiation therapy to reduce the size of the tumor, or as a palliative treatment for recurrent and advanced tumors.
Surgery is preferred as the main treatment when oral cancer is not sensitive to radiation therapy, when lymph nodes, salivary glands, or bone are involved, or when there is a recurrence of a tumor in a site that has already received a therapeutic dose of radiation. The disadvantage of surgery is the sacrifice of important, functional oral structures.
Acute physical complications after head and neck surgery may include any of the following: airway obstruction, fistula formation, necrosis in the surgical site, impairment of the senses (hearing, vision, smell, taste), impairment of swallowing and speech, and compromised nutritional status. Long-term complications include speech impairment, malnutrition from the inability to swallow foods, drooling, malocclusion, temporomandibular disorders, facial deformity, and chronic pain in the shoulder muscles.
There may be consequential psychological problems associated with surgery because the results of the treatment are often visible and can be devastating and humiliating. Physical impairments cannot be completely disguised by clothing, cosmetics, or prostheses. Consequently, some individuals experience depression, withdrawal, anger, and/or stigmatization. Surgical procedures for oral cancer result in long-term disability. These problems may be short-term if reconstructive surgery by an oral surgeon and rehabilitation are possible.
Chemotherapy is often used as an adjunct to another treatment option. Chemotherapy is the use of certain chemicals to interfere with cancer cell proliferation, eventually leading to apoptosis. There are six classes of chemotherapy drugs and each one affects the cell's chemistry differently, depending on location of the cancer and the stage in which the cells are in the cell cycle (Table 7).
Depending on the drug chosen, current chemotherapy will affect malignant cells in one of three ways:
|1.||Damage to the DNA of the cancer cells so they can no longer proliferate. This is done by alter- ing the DNA structure in the nucleus of the cell, thus preventing replication.|
|2.||During the S phase of the cell cycle, the chemo agent inhibits the synthesis of new DNA strands so that no replication is possible. This occurs when the drugs block the formation of nucleotides that are necessary for new DNA to be produced.|
|3.||Stop the mitotic processes of the cell so that the cancer cell cannot divide into two cells. The formation of the mitotic spindles is necessary to move the original DNA to the opposite sides of the cell so the cell can divide into two daughter cells.|
Chemotherapy is an effective way of killing malignant cells, but in the course of treatment normal cells are also killed. Once treatment has been completed, the non-cancerous cells will return to their normal function or be replaced by new healthy cells.
There are many side effects associated with chemotherapy that can bring discomfort and inconvenience. Most side effects are manageable, and are treatable if they do become problematic. Some common side effects include hair loss, mouth sores, gastrointestinal problems (nausea, constipation, diarrhea, loss of appetite), low blood cell counts, sore throat, rashes, fatigue, and infertility (temporary or permanent). One very important side effect is the effect chemotherapy has on bone marrow and the maturing red and white blood cells and platelets found there. The strong drug agents affect the quickly dividing marrow cells in the same way as the malignant cells. Decreased output of healthy red blood cells can lead to anemia, while a decreased output of white blood cells and platelets can lead to a compromised immune system and clotting and healing ability.
IMRT is a state of the art cancer treatment that delivers high doses of radiation directly to the cancer cells in a precise, targeted way, while sparing more of the surrounding healthy tissue. This has important advantages in oral cancer as it allows the beam to hit the target area while missing the surrounding structures such as the salivary glands and sinuses. IMRT uses computer-generated images for planning and then delivers a tightly focused beam to the cancerous tumor. Clinicians "paint" the tumor with the radiation beam, which conforms closely to the shape of the tumor. IMRT can be used to treat tumors that in the past have been considered untreatable given their close proximity to critical organs and structures. A powerful computer program optimizes a treatment plan based on tumor size, shape, location, and dose requirements from the physician. A medical linear accelerator, equipped with a special device called a multi-leaf collimator that shapes the radiation beam, delivers the radiation according to instructions. The equipment can be rotated to access the tumor from the most favorable vantage point. IMRT is currently being used to treat other tumors of the head and neck, brain, liver, lung, pancreas, prostate, and uterus.
Radiation therapy, also known as radiotherapy, is used in treating localized solid tumors, such as those in the head and neck. Before starting treatment, a CAT scan is done and measurements and markings are made on it in preparation of treating the tumor. A porous mesh mask is made for the patient to immobilize the head during treatment, and to prevent irradiation of healthy areas. The total dose of radiation is prescribed by a radiation oncologist and broken down into smaller doses to be given over a period of days. Most patients tolerate these smaller doses without an adverse effect on the maximum benefit. The treatment course is usually 2-8 weeks, allowing for normal tissues to repair after each exposure and minimizing permanent injury. Research is being conducted to increase the effectiveness of current techniques.
Recent radiotherapy research has focused on the use of radiolabeled antibodies to deliver doses of radiation directly to the cancer site. Some tumor cells contain specific antigens that trigger the body's immune system so that it produces tumor specific antibodies. Benefits of this approach include minimizing the risk to healthy tissues. Safe, but effective dosages and identification of appropriate radioactive substances are still being worked out. Side effects of radiation therapy include irritation of the tissue in the treatment area, xerostomia, infection, radiation-induced caries, trismus, alteration of taste, possible hair loss, and fatigue.
Osteoradionecrosis is a condition that affects bone healing and can occur in individuals who receive high doses of radiation during cancer therapy. This can occur after dental surgery or extraction of teeth. High doses of radiation can decrease the bone's blood supply, resulting in the decrease of oxygen to the area and eventual necrosis of bone tissue. The mandible is the most often affected area. Symptoms of osteoradionecrosis may occur months to years after radiation therapy with common symptoms including mouth pain, swelling of the jaw, and trismus. Treatment of osteoradionecrosis can vary from antibiotic therapy, local debridement, and in more severe cases removal of affected bone.
Prognosis is highly variable and dependent upon the stage and the location of the disease when first diagnosed. The more advanced stages will result in a lower survival rate. The survival rates for carcinomas of the base of the tongue (distal to the circumvallate papillae) are very low compared with those carcinomas on the oral portion of the tongue. The American Cancer Society reported in 2013 that the 5-year survival rate for stage I cancer of the lip is 96% whereas the 5-year survival rate for stage I cancer of the oropharynx and tonsil is only 56%. The public often does not comprehend the severity of oral cancer, perhaps because it associates diseases in the mouth with dental care that is not life threatening.
Ongoing research is being done in several areas of oral cancer at many university hospitals, medical centers and other institutions nationwide. Each year more is learned about the deadly disease. Current research is being done in the areas of DNA changes, gene therapy, new chemotherapy agents and radiotherapy methods, tumor growth factors, and vaccines.
Research in DNA Changes
Work is being done with the p53 gene and Human Papilloma Virus (HPV) DNA. Tests are being formed to detect p53 alterations, allowing for early detection of oral and oropharyngeal tumors. Tests are also being conducted for detection of HPV DNA in cells for earlier diagnosis of other forms of cancer.
Research in reversing DNA changes in oral cancer as a treatment is being conducted. Clinical trials involving p53 and its replacement with a normal gene to restore normal function to the cells currently are being conducted. Gene therapies to disrupt HPV replication also are being developed. Another type of therapy involves new genes being added to cancer genes to make them more susceptible to a particular type of drug in treating the particular type of cancer.
New Chemotherapy and Radiotherapy Methods
New drugs are being developed that are more effective against advanced oral cancer. Intraarterial chemotherapy (injection of drugs into the arteries feeding the cancer) is being tested in conjunction with radiation therapy. Advances in intralesional chemotherapy are being made. New methods are also being developed in radiotherapy that will reduce side effects and tissue/organ destruction.
Tumor Growth Factors
New drugs that recognize cells with too many Epithelial Growth Factors receptors are now being tested in clinical trials. These drugs also may boost the patient's immune system.
Vaccines are being investigated as a way to treat cancer patients by helping to boost their immune systems to recognize and attack cancer cells. Vaccines against the Human Papilloma Virus (HPV) have been developed. The vaccine, Gardasil®, is made up of proteins from the outer coat of the virus and does not contain any infectious material. Gardasil® protects against four types of HPV, attributing to 75% of the cervical cancer cases and 90% of genital warts. This vaccine, approved for use in females and males aged 9-26 years, is given through a series of three shots over a period of six-months. Studies have found Gardasil® to be almost 100% effective in preventing diseases caused by the four types of HPV covered by the vaccine, but less effective in individuals who had already been exposed. This vaccine is not used in treating existing HPV infections, genital warts, precancers, or cancers.
Dental Considerations for the Diagnosed Patient
It can be challenging caring for a patient who is undergoing cancer treatments or will be in the near future. Patient education is an essential part of the pretreatment assessment and should include a discussion of possible oral complications.
Prior to Treatment
A thorough exam of the hard and soft tissues:
|•||Reduces the risk and severity of oral complications|
|•||Allows for immediate identification and treatment of existing infections and other problems|
|•||Increases the probability that the patient will successfully complete the prescribed course of treatment|
|•||Reduces the likelihood of oral pain|
|•||Minimizes oral infections that could lead to potentially fatal systemic infections|
|•||Minimizes complications that compromise nutrition|
|•||Preserves or improves oral health by improving the quality of life and decreasing the cost of care in the future|
|•||Establishes a baseline for comparison post treatment|
The following measures should also be taken into consideration:
|•||Identify and treat existing infections, carious lesions, and other compromised teeth|
|•||Stabilize or eliminate potential sites of infection|
|•||In adults, extract teeth that may pose a future problem or are non-restorable to prevent later extraction-induced osteonecrosis|
|•||In children, consider extracting highly mobile primary teeth and teeth that are expected to exfoliate during the course of treatment|
|•||Perform oral surgery at least 2 weeks before any radiation therapy begins|
|•||Oral surgery should be performed at least 7 to 10 days before the patient receives myelosuppressive chemotherapy|
|•||Remove orthodontic bands and brackets if highly stomatoxic chemotherapy is planned or if the appliances will be in the radiation field|
|•||Prescribe an individualized oral hygiene regime to minimize oral complications|
|•||Patients undergoing head and neck radiation therapy should be instructed in the use of supplemental fluoride|
|•||If a removable prosthetic appliance is worn, make sure it is well adapted to the tissues and that the patient is able to wear and clean it daily; Instruct the patient to leave the appliance out at night|
Continued patient education is needed during and after cancer treatment. Instruction in adequate nutrition and avoiding alcohol and tobacco can prevent or decrease oral complications. Detailed instructions should be provided for the patient on specific oral health care practices such as how and when to brush and floss, how to recognize signs of oral complications, and other instructions appropriate for the individual. Instructions may include:
|•||Brush teeth, gums, and tongue gently with an extra-soft toothbrush and fluoride toothpaste after every meal and before bed; Bristles may be softened on the brush with warm water|
|•||Floss teeth gently every day; It is recommended that if gums are sore or bleeding, to avoid those areas and floss the other teeth|
|•||Avoid alcohol-containing mouth rinses, spicy or acidic foods, toothpicks, tobacco products, and alcoholic beverages|
|•||Avoid candy, gum, and soda unless they are sugar-free|
|•||Rinse the mouth with a baking soda-salt solution followed by a plain water rinse several times a day (Use 1/4 teaspoon of baking soda and 1/8 teaspoon of salt in 8 ounces of warm water)|
|•||Exercise the jaw muscles three times a day to prevent and treat jaw stiffness; Open as far as possible without causing pain and close the mouth; repeat 20 times|
|•||Follow instructions for using fluoride gel|
|•||Keep all appointments recommended by the dentist.|
Supplemental fluoride is often prescribed during cancer treatment as a fluoride gel delivered via custom trays. Fluoride rinses are not adequate to prevent demineralization. Several days prior to the start of radiation therapy, a daily regimen of a 5-minute application using 1.1% neutral pH sodium fluoride gel or 0.4% stannous fluoride should be started. Whether stannous or sodium fluoride is used, the patient should always use unflavored fluoride. Flavored fluorides can be irritating to already inflamed and possibly painful oral tissues. For patients with porcelain crowns, composite, or glass ionomer restorations, a neutral pH fluoride should be used to prevent damage to the restorations.
When using a tray to deliver the fluoride application, the following instructions should be given to the patient (Figure 11):
|1.||Place a thin ribbon of fluoride in each tray|
|2.||Place the trays on the teeth and leave in place for 5 minutes; If the gel overflows the tray, too much is being used and the amount should be reduced|
|3.||After 5 minutes, remove the trays and spit out any excess gel; Do not rinse|
|4.||Do not eat or drink for 30 minutes|
|5.||Clean the trays with a toothbrush and allow to air dry; Trays can be cleaned weekly in a denture cleaner following manufacturer's instructions|
For those patients reluctant to use a fluoride tray, a high-potency fluoride gel should be brushed on the teeth following daily brushing and flossing. Either 1.1% neutral pH sodium or 0.4% stannous fluoride gel is recommended, based on the type of dental restorations present in the mouth.
When using the brush-on method of application the following instructions should be given to the patient (Figure 12):
|1.||After brushing with fluoride toothpaste, rinse as usual|
|2.||Place a thin ribbon of fluoride gel on the toothbrush|
|3.||Brush for 2 to 3 minutes by the clock|
|4.||Spit out any excess gel at the end of the timed period; Do not rinse.|
|5.||Do not eat or drink for 30 minutes|
|6.||Rinse toothbrush well and allow to air dry|
Patients with radiation-induced salivary gland dysfunction must continue lifelong daily fluoride application to help preserve the dentition.
Once all complications of chemotherapy have been resolved, patients may be able to resume their normal dental care schedules. However, if the patient's immunity continues to be compromised, the patient's hematologic status needs to be determined before any dental treatment or surgery is initiated. This is particularly important to remember for those patients who have undergone blood/platelet transfusion therapies and marrow transplantation.
Patients who have completed radiation therapy to the head and neck and whose oral complications have decreased should be evaluates every 4 to 8 weeks for the first six months. Time intervals can be changed depending upon the patient's dental needs. It is, however, important to remember that oral complications may continue or appear long after radiation therapy has ended.
Continued research is needed in the fight against all cancers. Basic research has already paid off in many ways. Researchers know which specific classes of genes are involved in cancer development, that environmental factors can trigger genetic mutations, and that cancer cells can become out of control and proliferate without restraint. The general populace needs further education about changing lifestyle factors. Quitting all forms of tobacco use, stopping excessive use of alcohol, making sure dental appliances fit appropriately, and eating a diet rich in fruits and vegetables are all things people can do now to reduce their risk of developing the disease. Medical and dental professionals can save lives by consistently performing simple head and neck exams on all patients, and by discussing with them the early warning signs of oral cancer.
Head and neck exams should become the standard protocol for each new patient entering a practice, as well as for patients returning for routine care. The importance of a tobacco-free lifestyle should be addressed with patients who are current users. Various modalities should be incorporated into their care, whether it is prescribing a nicotine patch or a referral to a tobacco cessation clinic at a dental school or medical center.
adenopathy - any disease of the glands, especially of the lymphatic glands
allele - one of two genes containing inheritable characteristics
angiogenesis - the process that stimulates the formation of blood vessels
apoptosis - programmed death of cells
asymptomatic - without symptoms
basement membrane - a thin layer of delicate non-cellular material of a fine filamentous structure underlying the epithelium
benign - not recurrent or progressive; non malignant
carcinogenic - cancer causing
carcinoma - a new growth or malignant tumor that occurs in epithelial tissue; etiology is unknown.
centromeric - region of the chromosome that connects the chromatids during cell division
chromatid - one of two potential chromosomes formed by DNA replication
chronicity - failure to heal
clone - group of cells descended from a single cell
differentiation - the acquiring of individual characteristics
DNA - deoxyribonucleic acid; carrier of genetic information
down-regulate - to inhibit or suppress the normal response of a gene
dysplastic - abnormal development of tissue
epithelial - a type of tissue cell that forms the outer layer of skin and lines the inner cavities of the body; arranged in one to few layers and devoid of blood vessels
erythema - a red area of variable shape and size reflecting inflammation, thinness, and irregularity of the epithelium and lack of keratinization
erythroplakias - red lesions of the mucous membranes
etiology - the cause of the disease
extracellular matrix - the material outside of the cell
fixation - a non-mobile lesion occurring as a result of abnormally dividing cells invading to deeper areas and onto muscle and bone
free radicals - molecules that have split and now have an odd number of electrons; often repaired with antioxidants found in fruits and vegetables
hematogenous - originating in the blood
heterozygosity - possessing different alleles
immunosuppression - prevention of the activation of the immune responses
induration - hardness, primarily as a result of an increase in the number of epithelial cells from an inflammatory reaction that has spread into the surrounding tissue
innocuous - innocent
integrin - the receptor on cell surfaces that links with proteins and chemical mediators for cell-to-cell communication
Kaposis's Sarcoma - a vascular malignancy that is often first apparent in the skin or mucous membranes; the most common AIDS-related tumor; etiology is unknown but thought to involve immunosuppression
keratin - an extremely tough, but fibrous protein substance that may be hard or soft
keratinization - the process of keratin formation
lateral borders of the tongue - sides of the tongue
leukoplakia - a white patch on the mucosal surface
library - a large set of clones that collectively contain all the donor's DNA
localized - restricted to a limited area
lymphadenopathy - disease process affecting the lymph nodes resulting in the hardening and enlargement of the nodes
lymphoma - a usually malignant lymphoma neoplasm
malignant - cancerous growths resisting treatment
melanoma - a malignant tumor of the skin
metabolites - byproducts of metabolism
metalloproteinases - a protease bound to metal
metastasis - movement of cancerous cells from one part of the body to another
mutations - permanent variation in genetic structure
myeloma - a tumor originating in the cells of the bone marrow
neoplasm - a new and abnormal formation of tissue (tumor) that grows at the expense of the healthy organism
oncogenes - genes that have the ability to induce cell malignancy
oropharynx - the central portion of the pharynx lying between the soft palate and the upper portion of the epiglottis
p53 - a protein produced by a tumor-suppressor that is believed to play an important role in the birth and death of cells
protease - a class of enzymes that break down amino acid proteins
proto-oncogenes - normal cell genes before they become oncogenes
radiation induced caries - carious lesions that develop in reaction to head and neck radiation; during and following treatment, the patient experiences xerostomia, changes in salivary flow and perhaps difficulty in maintaining proper oral hygiene
squamous cell - a flat, scaly, epithelial cell
stage - period in the course of a disease such as cancer; the higher the number of the stage, the more advanced the disease
stomatoxic - toxicity to the oral cavity
telomerase - an enzyme present in cancer cells that allows them to divide indefinitely
transformation - changing of shape or form
trismus - a contraction of the jaw muscles as a result of oral infection, trauma, or inflammation of the salivary glands
tubulin - a protein present in cells
tumor - a spontaneous new growth of tissue forming a mass
tumor suppressor genes - genes that suppress the growth of a tumor
ulceration - loss of skin surface with a gray to yellow center surrounded by a red halo, resulting from the destruction of epithelial integrity owing to discrepancy in cell maturation, loss of intracellular attachments, and disruption of the basement membrane; formation of a sore (ulcer)
up-regulate - to increase or excite the normal response of a gene
ventral surface of the tongue - under side of the tongue
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About the Author
Natalie Kaweckyj, LDARF, CDA, CDPMA, COA, COMSA, CPFDA, CRFDA, MADAA, BA
Natalie Kaweckyj currently resides in Minneapolis, MN, where she is the Clinic Coordinator and Compliance Analyst for a nonprofit pediatric dental clinic. She is a Licensed Dental Assistant in Restorative Functions (LDARF), Certified Dental Assistant (CDA), Certified Dental Practice Management Administrator (CDPMA), Certified Orthodontic Assistant (COA), Certified Oral & Maxillofacial Surgery Assistant (COMSA), Certified Preventive Functions Dental Assistant (CPFDA), and a Master of the American Dental Assistants Association. She holds several expanded function certificates, including the administration of nitrous oxide/oxygen analgesia. Ms. Kaweckyj graduated from the American Dental Association-accredited dental assisting program at ConCorde Career Institute and has received a Bachelor of Arts in Biology and Psychology from Metropolitan State University. She is currently writing her dissertation for her master's in Public Health. She has worked clinically, administratively and academically. Ms. Kaweckyj is currently serving as on several ADAA Councils after having served on the ADAA Board of Trustees 2002 - 2012. She served as ADAA President in 2010-2011. She is the current Business Secretary and legislative chairman for the Minnesota Dental Assistants Association (MnDAA) and a three time past president of MnDAA. She also is a Past President of the Minnesota Educators of Dental Assistants (MEDA) and still an active member. In addition to her association duties, Natalie is very involved with the Minnesota state board of dentistry as well as with state legislature in the expansion of the dental assisting profession. She is a freelance writer and lecturer and is always working on some project. She has authored many other courses for the ADAA.