Cancer of the mouth and pharynx accounts for more than 30,000 cases of cancer per year in the United States and is the sixth most common cancer worldwide. More than 90% of these oral-pharyngeal cancers are squamous cell carcinomas. The five-year survival rate (approximately 50%) from oropharyngeal carcinomas has not significantly improved in the past 30 years.1,2 Higher survival rates are associated with early diagnosis, younger age, early cancers (stages I and II), anterior sites, cancer depth of 5 mm or less, and carcinomas that do not infiltrate bone. Recurrences are frequent, especially if patients fail to stop using tobacco and alcohol products.
Epithelial malignancies of the oral cavity often begin as pre-neoplastic lesions in the form of inflammatory lesions such as leukoplakia. Leukoplakia is associated with tobacco and alcohol use and chronic inflammation with the risk of malignant transformation to squamous cell carcinoma (SCC) of approximately 5-17%.3 In the year 2000, the American Cancer Society reported 30,200 cancers of the oral cavity and pharynx and 7,800 deaths because of this disease in the United States.4 The vast majority of oral cancers occur in patients over age 45 years, and the incidence increases with each decade over age 40 for men and women until age 65.4-5
Oral SCC has a variable appearance. It may be a white or red patch, an exophytic mass, an ulceration, a granular raised lesion, or combinations of these (Figure 1). White lesions that cannot be scraped off and are clinically non-specific, called leukoplakia, are potential precursor lesions. About 19% of leukoplakias are dysplastic, and about 4% are considered SCC at initial biopsy. Leukoplakias that are not cancerous when first biopsied have about a 6% chance of developing into cancer over time. Thus, the overall incidence of SCC in oral leukoplakia approximates 10%.
The malignant transformation rate for homogeneous and mixed leukoplakias is higher (as high as 17.5%). Leuloplakias with areas of erythema have a three to five time greater chance of being cancerous at initial biopsy or developing into cancer than do homogeneous leukoplakias.6-9 Non-specific red lesions involving the oral mucosa (erythroplakia), although less common than white lesions, are malignant in more than 60% of cases at initial biopsy.
The majority of early carcinomas are asymptomatic and have an erythroplastic component. Advanced lesions are more often ulcerated with raised margins, and pain is often absent until late in the course of the disease. High-risk sites include the floor of the mouth, lateral (posterior) and ventral (anterior) surfaces of the tongue, soft palate, and surrounding tissues. These areas are less keratinized and more susceptible to carcinogens. The buccal mucosa and gingiva also are common sites, especially in regions where social oral habits result in carcinogens being placed in close proximity to these tissues. Carcinoma of the upper lip and dorsum of the tongue (e.g., due to use of arsenic compounds) are rare.
Due to the nature of oral cancer, its poor prognosis, and the ability to slow or eradicate it with early treatment, it is important to detect pre-malignant lesions as well as very early carcinomas. Presently, there are several initiatives to assist the dental practitioner in the early detection and prevention of oral cancer.
Oral Cancer Campaign Launched
In June of 2003, the ADA launched a campaign urging dentists to examine patients for signs of early oral cancer. Approximately 30,000 new cases of oral cancer are diagnosed each year in the United States. According to the American Cancer Society, oral cancer occurs almost as frequently as leukemia and claims almost as many lives as melanoma cancer.
Routine, careful examination of patients is appropriate and necessary. This can easily be achieved during a regular dental visit. The stage at which an oral cancer is diagnosed is critical to the course of the disease. When detected at its earliest stage, oral cancer is more easily treated and cured. When detected late, the overall five-year survival rate is about 50%.
The campaign was featured at the ADA’s Annual Session in San Francisco in October 2003 and will run through 2006. The ADA is working with state and local dental societies to promote education and awareness among its members. The effort will feature a series of activities targeted to dentists, dental schools, patients, and consumers.
CDx Laboratories, providers of OralCDx, a computer-assisted, painless brush biopsy oral cancer detection test, is supporting the campaign through an unrestricted educational grant. After a year of planning and preparation, the ADA’s oral cancer prevention continuing education course is on its way to a location near you.
“Dentist Saves Patient’s Life: Early Oral Cancer Detection and Tobacco Use Cessation”, which debuted at the Annual Session in San Francisco in October 2003, was developed by the ADA and prominent researchers thanks to a $1.2 million grant from the National Cancer Institute. The course will be presented a total of 50 times at locations nationwide between January 2004 and December 2006.
Oral cancer affects more than 27,000 Americans each year, including more than 18,000 men, and claims the lives of nearly 8,000 people, according to the American Cancer Society.
Nearly half of all patients who develop oral cancer don’t survive five years — a statistic that hasn’t improved in the last two decades — so through the grant from NCI, the ADA convened a panel of experts to design a course that focuses on early detection of oral cancer and prevention through tobacco use cessation using techniques and information that dentists can use in everyday patient care.
Dr. Sol Silverman, Professor of Oral Medicine at the University of California-San Francisco School of Dentistry, and Dr. Kathleen Vendrell Rankin, Professor and Vice-Chair of the Department of Public Health Sciences at Baylor College of Dentistry, presented the premier course to a standing-room-only crowd of more than 200 at the Annual Session.
Dr. Silverman, principal investigator for the grant, and Dr. Rankin, grant collaborator, worked closely with the expert panel in developing the course.
“Based on feedback from course attendees, as well as the enthusiasm of dental organizations throughout the country to include our program in their educational courses,” said Dr. Silverman, “we are optimistic in reaching the grant goals.”
The course’s goals are to increase the number of dentists who provide oral cancer screenings and detect oral cancer in its earliest stages and to increase the number of dentists who practice tobacco cessation.
Dentists who take this five-hour course will learn the cutting edge diagnostic techniques, skills for early clinical recognition of oral cancer and precancerous lesions, risk factors for oral cancer, and the latest tobacco use cessation therapies.
Lesion Identification
The tongue is the most common site for oral cancer in both American men and women. The most recent data (2004) indicates that about 37% (7,320:20,010) of all oral cancer (excluding the pharynx) occurs on the tongue.5 Oral tongue malignancies (located in the anterior two-thirds) accounted for 53% of tongue cancer.5,6 The other oral anatomical sites in decreasing order are: lip, 22%; floor of mouth, 13%; salivary glands, 12%; buccal mucosa, 6%; gingiva, 6%; and palate, 4%.
Clinical Examination
A comprehensive oral examination on every patient is essential to dental practice. The standard-of-care examination includes not only thorough examination of every intraoral mucosal surface, but the extraoral head and neck tissues including lymph nodes as well.10-15 Any mucosal abnormality requires some action plan, whether that includes treatment, biopsy, referral, or recall examination, and will depend upon the nature of the lesion. Many oral lesions are ill-defined, variable-appearing, controversial, and poorly understood lesions which fortunately are benign, but may present changes that may easily be confused with malignancy. Conversely, early malignancy may quite often be mistaken for a benign lesion. Some lesions are considered pre-malignant because they are statistically correlated with subsequent associated cancerous changes.10-15
It is understandable that there is a considerable amount of clinical uncertainty involved in the early detection of malignancy as well as in the understanding that many of these lesions may not always remain benign. Oral cancer may clinically present with different colors and morphologies. Oral cancer may appear as leukoplakia (white), erythroplasia (red), erythroleukoplakia (red and white most common), and as plaques, macules, ulcers, exophytic papules, nodules or tumors, and granular and/or verrucous lesions. Often, squamous cell carcinomas present with very pleomorphic characteristics combining several of these features, and may or may not be fissured, indurated, and bleeding.15-18
During the earliest stages, oral cancer is usually painless or may present with only mild irritation. Pain usually occurs when the lesion becomes more advanced and ulcerated. Ulceration indicates that the lesion has penetrated through the lamina propria into the connective tissue. Rarely, a patient may seek initial consultation because of a swelling in the neck that represents a metastasis from an oral lesion of which the patient may be completely unaware. The following are common identifying techniques of oral carcinoma.15-18
Toluidine Blue
Because epithelial dysplasia and early squamous cell carcinoma vary considerably in appearance and often resemble certain benign lesions, clinical identification is difficult, and biopsy is frequently delayed by attempts at empirical remedies. Vital staining with toluidine blue has been shown to aid early recognition and accelerate biopsy, diagnosis, and treatment. Toluidine blue is a metachromatic dye of the thiazine group that has been effectively used as a nuclear stain because of its binding to DNA. Overall accuracy of the toluidine blue uptake was 93%. It can be concluded that toluidine blue staining is a useful adjunct to careful examination, clinical judgment, and biopsy. There is abundant evidence that toluidine blue dye used in this diagnostic manner is neither mutagenic nor carcinogenic.15-18
Visilite
The application of acetic acid for visual examinations of the oral mucosa along with the use of a special light is a diagnostic technique which has been successfully used in gynecology, where it is known as colposcopy. The light emitted from a special small (size of a dental handpiece) lamp causes oral lesions which have pre-cancerous potential to appear very opaque-white. The acetic acid binds to those cells that show hyperkeratosis, and the light simply makes them easier to see. It is also helpful in determining where the borders of the suspicious lesion extend. These lights are included in a diagnostic kit and marketed in the U.S. as Visilite®. Their effectiveness in diagnosing oral cancer has yet to be determined.15-18
Imaging
Most commonly, neoplasms of the oral cavity and oropharynx are discovered by clinical examination and confirmed by biopsy or fine needle aspiration (FNA). Imaging studies may then be employed to map the extent of disease, detect bone invasion and crevical adenopathy, and evaluate adherence of tumor to the carotid artery. Occasionally, a patient may present with cervical nodal metastases without a clinically evident primary lesion. In this setting, cross-sectional imaging obtained prior to panendoscopy and biopsy is useful to locate submucosal tumor and direct biopsies to possible targets. The detection of recurrent disease following therapy may also be facilitated by cross-sectional imaging. The advanced imaging techniques presently available include computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Ultrasonography, often in conjunction with FNA biopsy, may also be useful.15-18
Follow-up
Because many methods of managing leuoplakia are not always feasible or effective, these patients must be observed periodically. The follow-up examination should be frequent (< 6 months) depending upon the actual diagnosis and clinical scenario. The follow-up examination includes careful clinical observation and an occasional biopsy.15-18 Follow-up biopsy is indicated when changes in signs and/or symptoms occur. These changes may be subtle. Exfoliative cytology using the brush biopsy technique and vital staining with toluidine blue help supplement clinical judgment and serve as an adjunct to biopsy. Because the “gold standard” for diagnosis is tissue biopsy with histopathologic examination, the value of adjunctive techniques is to accelerate microscopic evaluation by indicating the need of biopsy in situations in which a biopsy is delayed or not thought to be indicated or necessary. Negative smears or stains must be balanced with good clinical judgment. Therefore, if clinical suspicion persists in a lesion that does not disappear, a standard scalpel biopsy must be considered.
Patient Education Initiatives
In two recent studies (Epstein 2003 and Rhodus 2003), only 11% of dental patients said that they had received an oral cancer examination from their dentist. While it is extremely likey that the dentist indeed performed the oral cancer examination, the patients were not made aware of it. The American Dental Association in conjunction with the American Cancer Society has launched an aggressive patient/public education campaign oriented toward providing the public with more information about oral cancer and promoting frequent dental check-ups, as oral cancer is dentistry’s responsibility to detect.
This program offers the following information to patients and is being distributed via billboards, radio spots, newspapers, and magazines across the U.S. It is important for dentists to be aware of the information being distributed to the public in order to respond to questions or concerns.
The Importance of Early Detection
Your dentist has recent good news about progress against cancer. It is now easier than ever to detect oral cancer early, when the oportunity for a cure is great. Currently only half of all patients diagnosed with oral cancer survive more than five years.
Your dentist has the skills and tools to ensure that early signs of cancer and pre-cancerous conditions are identified. You and your dentist can fight and win the battle against oral cancer.
Know the early signs and see your dentist regularly.
You Should Know
• Oral cancer often starts as a tiny, unnoticed white or red spot or sore anywhere in the mouth.
• It can affect any area of the oral cavity, including the lips, gum tissue, cheek lining, tongue, and the hard or soft palate.
• Other signs include:
- A sore that bleeds easily or does not heal.
- A color change of the oral tissues.
- A lump, thickening, rough spot, crust, or small eroded area.
- Pain, tenderness, or numbness anywhere in the mouth or on the lips.
- Difficulty chewing, swallowing, speaking, or moving the jaw or tongue.
- A change in the way the teeth fit together.
- Oral cancer most often occurs in those who use tobacco in any form.
- Alcohol use combined with smoking greatly increases risk.
- Prolonged exposure to the sun increases the risk of lip cancer.
- More than 25% of oral cancers occur in people who do not smoke and have no other risk factors.
- Oral cancer is more likely to strike after age 40.
- Studies suggest that a diet high in fruits and vegetables may prevent the development of potentially cancerous lesions.
Regular Dental Check-Ups Important
Regular dental check-ups, including an examination of the entire mouth, are essential in the early detection of cancerous and pre-cancerous conditions. You may have a very small but dangerous oral spot or sore and not be aware of it.
Your dentist will carefully examine all areas of your mouth. In about 10% of patients, the dentist may notice a flat, painless, white or red spot or a small sore. Although most these are harmless, some are not. Harmful oral spots or sores often look identical to those that are harmless. Testing can tell them apart. If you have a sore with a likely cause, your dentist may treat it and ask you to return for re-examination.
Dentists often will notice a spot or sore that looks harmless and does not have a clear cause. To ensure that a spot or sore is not dangerous, your dentist may choose to perform a simple test, such as a brush biopsy, which usually is painless and can detect potentially dangerous cells when the disease is still at an early stage. If your dentist notices something that looks very suspicious and dangerous, a scalpel biopsy may be recommended. This usually requires local anesthesia. Your general dentist may perform this procedure or refer you to a specialist for it.
University of Minnesota Oral Pre-Cancer Initiative
The University of Minnesota Divison of Oral Medicine and Department of Otolaryngology have formally established a Head and Neck Preneoplasia Clinic for the coordinated diagnosis and care of patients with head and neck preneoplasia. This collaborative effort is endorsed and supported by the Comprehensive Cancer Center and the Oral Health Research Center of the University of Minnesota and is located on the 7th floor of the School of Dentistry in the Oral Health Research Center.
Currently there is not a well established care plan for patients diagnosed with pre-neoplastic lesions of the head and neck. Additionally, there are no published or accepted pre-neoplasia models in cell lines or animals that are adaptable to human head and neck carcinogenesis. Therefore, there is minimal comprehension of the biology underlying factors that cause these cancers to form in upper aerodigestive mucosa. Without understanding the biology of the disease, it is extremely difficult to establish targeted treatment strategies to prevent the progression of upper aerodigestive dysplasia to frank cancer.
The range of care options for these lesions clinically may involve watchful waiting for these lesions to become malignant or radical excision or full course radiation of areas like the tongue or larynx for extensive cases of the pre-neoplastic disease state. However, watchful waiting of this disease process is not proactive and is unacceptable to many patients. It is very difficult psychologically and is frightening for many patients with this condition to wait for it to become cancer before action is taken. Conversely, radical treatment like laryngectomy and partial glossectomy or full course radiation are inelegant, morbid procedures for a disease state that is not invasive cancer. Additionally, long-term morbidities from these care plans may be severe, and because of field cancerization may not be effective.
Head and Neck Carcinogenesis Program at the University of Minnesota
As a joint effort of the University of Minnesota Cancer Center, the Departments of Otolaryngology, Oral Medicine, and Molecular Oncology this program has been established. This program is actively engaged in preclinical research in head and neck carcinogenesis in the laboratory with translation to the clinic. The primary focus of the laboratory involves the hypothesis that head and neck carcinogenesis is a multi-step process resulting from genotoxic damage to DNA by tobacco carcinogens accompanied by injury response mechanisms resulting in chronic inflammatory stimuli that are associatied with the upregulation of the malignant phenotype. Therefore, there is a focus not only on the events that are associated with carcinogenesis, but also on its intervention with pharmacologic agents that have anti-inflammatory effects or that help to reverse the process by causing the pre-malignant cells to become more mature.
The program has been very fortunate to attract clinical trial funding from both the NCI/NIH and industry to support innovative clinical trials designed to examine both anti-inflammatory and maturational strategies for the lining tissues of the mouth which are diseased with pre-cancerous conditions. Dr. Frank Ondrey has led these studies, including some cancer chemoprevention clinical trials. Recently, other studies have been proposed for funding or are ongoing that involve the author and others to examine pre-neoplastc tissues from patients in a genetic high thoroughput fashion using state-of-the-art gene chip technologies available to Dr. Patrick Gaffney of the University of Minnesota Cancer Center. These studies
will allow the examination of the hypothesis that early response gene activation occurs during head and neck carcinogenesis in patients and transformed squamous cells and that genes that are activated during processes like inflammation are turned on during this process. This will give supportive evidence to the continued use of anti-inflammatory strategies for the prevention of the development of cancer in these high risk patients with leukoplakia or oral dysplasia. The author is additionally involved in several projects designed to examine inflammatory mediators in saliva and other oral fluids to potentially exploit their use as non-invasive biomarkers of responses to chemoprevention drugs or even chemotherapy or radiation therapy effects.
Mission Statement
The Head and Neck Preneoplasia Program will provide consistent, comprehensive, high quality patient care serving the diverse needs of patients all across the Upper Midwest region with head and neck preneoplasia and provide state-of-the-art follow-up and potential participation in NIH or industry-sponsored clinical trials and multi-disciplinary follow-up to serve the unique needs of patients at risk for aerodigestive cancers.
Head and Neck Preneoplasia Clinic
This clinic is currently involved in the diagnosis and treatment of oral precancerous lesions employing funded clinical trials, observation, chemoprevention, or radiation-surgical intervention for frankly malignant lesions. Currently there is no specific infrastructure for diagnosing and following oral preneoplastic lesions. Patients are randomly referred or simply present to the clinic. An additional clinical trial is funded for the early diagnosis of oral cancer recurrence utilizing a simple oral dye stategy that may become commercially available for general use after the conclusion of the trial.
The clinic will be staffed by Dr. Nelson Rhodus and Dr. Frank Ondrey and hopefully faculty from Oral Pathology and others as well as Oral Medicine residents and perhaps Otolaryngology residents, with the assistance of ENT nurses as well as the Primary Clinical Trials nurse and research coordinator.
It is expected that the clinical activities of this entity will expand once the clinic is formally designated and promoted regionally. It is hoped that the Otolaryngology Department and the Comprehensive Cancer Center of the University of Minnesota will actively endorse, advertise, and participate in this preneoplasia program.
The new Head and Neck Preneoplasia Clinic will be located primarily in the Oral Health Research Center of the 7th floor of the School of Dentistry, although certain patients may necessarily be seen in the 8th floor PWB-Otolaryngology clinic. This will occur as currently designed protocols to translationally examine head and neck cancer are approved and funded.
References
1. Jemal A, Tiwari R, Murray T, Ghafoor A et al. CA: A Cancer Journal for Clinicians 2004;54:108-25.
2. Edwards BL, Howe HL, Ries LA et al. Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden. Cancer 2002;94:2,766-92.
3. Ries LA, Eisner MP, Kosary CL, Hankey BF et al. SEER Cancer Statistics Review, 1975-2000. Bethseda, Maryland: National Cancer Institute, 2003.
4. Myers JN. Elkins T, Roberts D, Byers RM. Squamous cell carcinoma of the tongue in young adults: increasing incidence and factors that predict treatment outcomes. Otolaryngol Head Neck Surg 2000;122:44-51.
5. Schantz SP, Yu G-P. Head and neck cancer incidence trends in young Americans, 1973-1997, with a special analysis for tongue cancer. Arch Otolarygol Head Neck Surg 2002;128:268-274.
6. Shiboski CH, Shiboski SC, Liverman S Jr. Trends in oral cancer rates in the United States, 1973-1996. Community Dent Oral Epidemiol 2000;28:249-256.
7. Silverman S Jr. Demographics and occurrence of oral and pharyngeal cancers: the outcomes, the trends, the challenge. JADA 2001;132:7S-11S.
8. Silverman S, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. Cancer 1984;53:563-568.
9. Young MRI, Wright MA, Lozano Y, Prechel MM et al. Increased recurrence and metastasis
in patients whose primary head and neck
squamous cell carcinomas secreted granulocyte-macrophage colony stimulation factor and contained CD34+ natural suppressor cells.
Int J Cancer1997;74:69-74.
10. Gleich LL, Biddinger PW, Duperier FD, Gluckman JL. Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma: a clinical-pathologic correlation. Head Neck 1997;19:276-280.
11. Pak AS, Wright MA, Matthews JP, Collins SL et al. Mechanisms of immune suppression in patient with head and neck cancer: presence of CD34+ cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res;
1995 (I):95-103.
12. Smith CW, Chen Z, Dong G, Loukinova E et al. The host environment promotes the development of primary and metastatic squamous
cell carcinomas that constitutively express proinflammatory cytokines IL-1 alpha, IL-6, GM-CSF
and KC. Clin Exp Metastasis 1998 Oct;16(7):655-664.
13. Vlock DR, Arnold B, Humpierres J, Schwartz DR et al. Serial studies of autologous antibody reactivity to squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 1992;34:329-336.
14. Landis S, Murray T et al. Cancer statistics. CA Cancer J for Clin 1998;48:6-29.
15. Little JW, Falace DA, Miller CS, Rhodus NL. Cancer. Dental Management of the Medically Compromised Patient, Sixth Edition. St. Louis: Mosby Inc. 2002, pages 394-412.
16. Clayman GL, Lippman SM, Laramore GE, Hong WK. Head and Neck Cancer. Holland JF, Frei E, Bast RC Jr., Kufe DW et al eds. Cancer Medicine. Philadelphia: Williams and Wilkins 1996;1,645-1,709.
17. Califano J, van der Riet P, Westra W, Nawroz H et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996 June 1;56(11):2,488-2,492.
18. Silverman, S Jr. Oral Cancer. Fifth Edition. BC Decker, Inc. Hamilton, Ontario-London. 2003, pages 11-28.
19. Forastiere A, Koch W , Trotti A, Sidransky D. Head and neck cancer. N Engl J Med 2001;345:1,891,900.
19. 20. National Cancer Institute. Risks associated with smoking cigarettes with low machine-measured yields of tar and nicotine. Smoking and tobacco control monograph no. 13. Bethesda, Maryland, 2001.
20. 21. Lewin F, Norell SE, Johansson H et al. Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck. Cancer 1998;82:1,367-1,375.
21. 22. Mashberg A, Garfinkel L, Harris S. Alcohol as a primary risk factor in oral squamous cell carcinoma. CA Cancer J Clin 1981; 31:146-155.
22. 23. Silverman S Jr, Bahl S. Oral lichen planus update: clinical characteristics, treatment responses and malignant transformation. Am J Dent 1997;10:259-263.
