Oral Cancer: Early Detection and Prevention

Oropharyngeal cancer accounts for nearly 30,000 cases of cancer (incidence of 10 per 100,000) and approximately 7,200 deaths per year in the United States, and is the sixth most common cancer worldwide.¹ Oral cavity cancer accounts for about 17,000 of these cases per year and is more common than leukemia, Hodgkin’s lymphoma, brain, stomach, or ovarian cancer. The 5-year survival rate from oral carcinomas has not significantly improved in the past 30 years, remaining at approximately 50%. The 5-year survival rate for whites is approximately 55%, while for blacks it is only 31%.¹

The ratio of men to women diagnosed with oral cancer is 2:1 over the lifetime, although the ratio comes closer to 1:1 with advancing age (and perhaps the relationship of human papilloma virus [HPV] to oral cancer). Approximately 96% of oral cancer is diagnosed in persons over the age of 40 and more than 50% of all cancers occur in persons over the age of 65.² The average age at the time of diagnosis is 63 years.¹ However, recent evidence has emerged indicating that oral cancers are occurring more frequently in younger persons (those under 40 years old).^3,4 The overall incidence of oral cancer has remained stable, relative to the occurrence of newly diagnosed cancers of all sites, with absolute numbers only slightly increasing each year.^5,6

More than 90% of these oropharyngeal cancers are squamous cell carcinomas. The other 10% are comprised of salivary gland tumors, lymphoma, sarcoma, and others. These malignancies of the oral cavity often begin as preneoplastic lesions in the form of inflammatory lesions such as leukoplakia, erythroplasia, and erythroleukoplakia. 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% to 17%.^7,8 These premalignant lesions may ultimately transform to cancer; especially if they demonstrate epithelial dysplasia. If so, the rate of cancer transformation may become as high as 42%.⁹ Alterations in host immunity, inflammation, angiogenesis, and metabolism have been noted to be prominent clinical features in oral cancer.^8,9

 

Anatomic Sites

The tongue is the most common site for oral cancer in both American men and women. The most recent data indicates that about 37% (7,320:20,010) of all oral cancer (excluding the pharynx) occurs on the tongue.¹ There are some differences in the most common oral sites in other areas of the world, such as Southeast Asia, where nasopharyngeal cancer is more common, and in India, where buccal mucosa carcinomas are the most common. Data from the SEER Program demonstrate that 30% of all oral cancers diagnosed in the United States between 1985 and 1996 occurred in the tongue, followed by the lip and floor of the mouth.^4,5 Oral tongue malignancies (located in the anterior two thirds) accounted for 53% of tongue cancers.^5,6 The other oral anatomical sites in decreasing order are: lip (22%), floor of mouth (13%), salivary glands (12%), buccal mucosa (6%), gingival (6%), and palate (4%).¹⁰

 

Stage at Diagnosis and Survival Rates

Unfortunately, only about half of all patients with oral and pharyngeal cancers will survive the disease 5 years after treatment. These statistics are even worse for carcinoma of the tongue, which is only about 33%.^5-9 In the United States the 5-year survival rates are more favorable for whites than for blacks (58% vs 34%). Genetics certainly is significantly involved in the predisposition to cancer, but socioeconomic status, education, and access to the healthcare system also have an influence.^5-7 Obviously, the survival rates for advanced tumors are much lower compared with earlier-detected, localized cancers. At the time of diagnosis, nearly 50% of all carcinomas of the tongue have already metastasized.¹⁰ An additional 35% to 40% will metastasize within 5 years. If all cases of oral cancer were diagnosed and treated early as localized tumors, almost 80% of all patients would survive to 5 years.^10-11 This is a major reason why detection of oral cancer as early as possible and/or prevention of the premalignant lesion from progressing to carcinoma are so important. Unfortunately, very little progress has been made during the past 40 years in regard to early diagnosis. Additionally, based on more than 25,000 SEER Program oral/pharyngeal cases for which there was adequate information, localized/early oral cancers were outnumbered by advanced tumors 59% to 41%. The lip was the only major site where localized cancers were more frequently found than more advanced cancers.^4-6 Advances in the treatment of oral cancer have not led to significantly improved survival; therefore, earlier diagnosis is obviously the most important factor in improving oral cancer control and reducing morbidity and mortality.^5-7

 

Etiology and Risk Factors

The etiology of oral cancer is apparently multifactorial and involves many alterations in host immunity, metabolism, angiogenesis, and exposure to chronic inflammation in a genetically susceptible individual that accumulate over time. The carcinogenic changes may be influenced by oncogenes, carcinogens, and mutations caused by chemicals, viruses, irradiation, drugs (tobacco and alcohol), hormones, nutrients, or physical irritants.^7,12,13

 

Tobacco

Reports from the US Surgeon General and others conclude that cigarette smoking is the main cause of cancer mortality in the United States, contributing to an estimated 30% of all cancer deaths and substantially to cancers of the head and neck.^4,7,14

The association between cigarette use and oral carcinoma has been firmly established from epidemiologic studies, revealing that there are more than twice as many smokers among oral cancer patients as among control populations.¹⁴ One study found that 72% of more than 400 patients with oral cancer were smokers and that 58% of them smoked more than one pack daily, demonstrating the very high risk for tobacco users.¹⁵ Tobacco use also increases the already high risk for developing recurrences of oral cancer as well as second primary oral and pharyngeal cancers.^14-16 The combined effects of tobacco and alcohol are illustrated in another study of over 350 patients who had oral cancer and a mortality rate of 31% within 5 years.¹⁷

Alcohol intake has also been associated with the incidence of oral cancer, especially with long-term excessive use. One group of investigators found that 44% of 108 patients with cancer of the tongue and 59% of 68 patients with cancer of the floor of the mouth, palate, or tonsillar fossa had unequivocal evidence of alcoholic cirrhosis. Approximately 75% drank alcohol excessively.¹⁷ However, definitive associations between alcohol-containing mouth rinses and the development of oral cancer have not been established.¹⁴

 

Nutrition

Although some studies indicate a potential association with dietary factors and cancer in general, there are no clear dietary characteristics (deficiencies or excesses of nutrients) which have been recognized that directly correlate with cancer of the oral cavity.^14,18

 

Viruses

While the role of viruses in the development of oral cancer is not known to cause oral squamous cell carcinoma, other head and neck cancers have a defined relationship with viruses. Of the viruses that infect oral tissues, those having oncogenic potential are from two groups: the herpes viruses and the papilloma viruses.^19-21 Among the most likely candidates to be causative of oral cancer (at least in part) are the human papilloma viruses, especially HPV type.^12,19-21

 

Clinical Examination

A comprehensive oral examination of every patient is essential to good dental practice and for the early detection of oral cancer or premalignant lesions. The standard-of-care examination includes not only a thorough examination of every intraoral mucosal surface, but the extraoral head and neck tissues, including the lymph nodes.^14,22 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.²² Many oral lesions are ill-defined, variable-appearing, controversial, poorly understood, and, fortunately, are also benign, but may present changes that could easily be confused with malignancy. Conversely, early malignancy may quite often be mistaken for a benign lesion. Some lesions are considered premalignant because they are statistically correlated with subsequent associated cancerous changes.¹⁴ 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, tumors, or 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.^14,22-25

 

Delay in Diagnosis

In a retrospective study, this author and Haws found that only 14.1% of dentists who had diagnosed a patient with epithelial dysplasia (considered premalignant) followed that lesion with a second biopsy during a 3-year period.²⁶

Unfortunately, often the diagnosis of oral cancer may be delayed because a clinician did not suspect the malignant nature of the lesion and either failed to treat it or treated it inadequately.^14,23-24 Most reports reveal that patients usually delay seeking professional advice for more than 3 months after having become aware of an oral sign or symptom. Such delays in diagnosis can only lead to local extension of a lesion and increase the risk of metastatic spread of the cancer.^14,22--23

 

Signs and Symptoms

During its earliest stages, oral cancer is usually totally asymptomatic or it 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.^14,22-23 See Table 5 for common presenting signs of oral carcinoma.¹⁸

The risk of subsequent malignant transformation increases when a biopsy specimen reveals an associated epithelial dysplasia. Current scientific consensus is that this transformation occurs in a stepwise fashion through stages of increasingly severe epithelial dysplasia accompanied by the loss of cell cycle control, apoptosis, and various genetic aberrations.^27-32 However, specific data regarding the correlation among degrees of oral epithelial dysplasia, time-related progression, and the influences of a variety of cofactors remain uncertain.^27-31

 

Oral Carcinogenesis

In oral epithelial tissues, accumulating mutations (ie, genetic progression), chromosomal damage and loss of cellular control functions are observed during the course of sequential histologic changes which culminate in oral cancer.^27-32 These changes are manifested as the transition from normal histology to early intraepithelial dysplasia and preneoplasia, through increasingly severe intraepithelial neoplasia to superficial cancer and finally, invasive disease.

 

Once the diagnosis of dysplasia is made there is really no way of determining which dysplasias will transform into carcinoma and which will not. Usually then, it may be safely assumed that severe epithelial dysplasia will most likely proceed to carcinoma in situ, intraepithelial carcinoma, and/or frank malignancy over time.

When the dysplasia of the entire epithelium involves disruption of the basal lamina and subsequent invasion of the adjacent connective tissue, the diagnosis of malignancy is certain.

Many studies are presently being conducted regarding the role of chromosomes and genes in influencing the development and progression of oral leukoplakia to malignancy. DNA microarray studies of gene expression are now being used to determine the differential profile of genes that are expressed in both oral cancer as well as precancerous (leukoplakia) lesions. Ginos and colleagues at the University of Minnesota have found that there were 2,891 genes differentially expressed in tissues of patients with oral cancer; the categories of genes included those involved in the host immune response, angiogenesis, apoptosis, and cell differentiation, among others.³³ The same group is now using microarrays to analyze not only tissues from premalignant lesions, but also using cytological smears.³³ Results from these important studies will aid in identifying risks and prognoses.

 

Diagnosis and Management

Patients with leukoplakia or other premalignant lesions and even early squamous cell carcinoma are usually asymptomatic.^24,34-35 The lesion is usually discovered by a clinician during a routine examination or by patients themselves because of a feeling of roughness in their mouths. There are really no reliable clinical signs and symptoms associated with oral leukoplakia that relate to an accurate prediction of a premalignant or early malignant change.^7,18,30 However, even mild symptoms are often suggestive of a dysplastic epithelial change or even an early invasive tumor. Because the clinical appearance of oral leukoplakia—thick or scant, large or small—does not reliably indicate its biologic potential, clinicians should be suspicious of all white lesions and should carefully evaluate and observe these patients.^7,14,24,34 The diagnosis of these lesions must be made by histopathologic evaluation.

 

The first step in the management of leukoplakia is the removal of all irritants. If the leukoplakia is not reversible, excision is the most effective treatment.^24,34-35 Excisional biopsy with subsequent histopathological examination is the gold standard of diagnosis for oral lesions.^14,34-35 However, because these lesions may spread over a large area, they cannot always be surgically excised. In many cases, incisional biopsies must be taken and may require multiple-site biopsies in the areas of the lesion that are phenotypically most suspicious for oral cancer.³⁶ In addition, recurrence after excision is common, possibly owing to continuation of an irritant or the biologic potential in adjacent tissue that appears morphologically normal (field cancerization). Some areas of the lesion may be cancer, while others may not. Therefore, representative sampling is important in making the diagnosis. The use of the carbon dioxide laser has proved extremely useful and effective.^36-37

However, it must be remembered that there is always some degree of risk, not only for recurrences but also for the development of squamous cell carcinoma at the surgical site. Therefore, close follow-up must be emphasized. To help limit recurrences, adjunctive chemotherapy using antiviral drugs and antioxidants is being studied.^38-39

Although there might be a “field keratinization,” or genomic susceptibility for hyperkeratosis, there is some evidence of clonal derivation. This is seen at times when a portion of a leukoplakic lesion is removed and the residual clinical lesion disappears.^27,33

 

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. To better visualize any abnormal oral lesion, clinicians may be able to use a tissue conditioning technique (with acetic acid) followed by the use of an ultraviolet fluorescent light that makes the lesion appear very white. Vital staining with tolonium chloride (toluidine blue) has been shown to aid early recognition and accelerate biopsy, diagnosis, and treatment.^40-41 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%.^40-41 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.^40-41

 

 

Cytology and Brush Biopsy

It is not practical or appropriate to biopsy every oral lesion often even after it has been diagnosed with epithelial dysplasia.^36,42 A simple, reliable, and acceptable technique to support the healthcare professional’s clinical judgment in differentiating benign lesions from early malignant neoplasia is highly desirable.

This is especially true when the clinician has already obtained a nondiagnostic biopsy and now wishes to follow up on the lesion using a noninvasive technique. Transepithelial cytology is a technique that serves this purpose, but it must be remembered that cytology is an adjunct to, not a substitute for, a scapel biopsy.^14,36 Transepithelial cytology is a technique by which individual epithelial cells (ideally including basal cells) are obtained from a lesion, spread on a slide, fixed, stained, and then examined by microscopy.^36,42 The entire oral cavity is lined with stratified squamous epithelium that varies in thickness and keratinization according to anatomic and functional sites. Transepithelial sampling using a specially designed brush to obtain representative cells from all epithelial layers of a specimen can be accomplished with the proper brush and technique.^36,42 The brush biopsy technique and oral cytology examination can provide a significant adjunct in the evaluation of questionable lesions by giving clinicians an initial screening tool before indicating the use of scalpel incisional biopsy of lesions that had not clinically appeared to be oral cancer. Results from these brush biopsies have indicated the early diagnosis of malignancies that would otherwise have remained unsuspected. A thorough examination of the cell sample is made by an automated microscopic system or by a trained cytologist and certified by a pathologist.^36,42

Classification of benign oral diseases from exfoliative cytologic studies is not yet possible; tissue patterns as seen in biopsies are still necessary. There is a possibility of false-positive and false-negative results, but reports of those have been few. These errors, though undesirable, are manageable because of the manner in which cytologic reports are used and interpreted: (1) if clinical suspicion remains in the face of a negative or atypical report, a biopsy should be performed in any case; (2) a suspicious report indicates a definite need to establish a definitive diagnosis immediately; and (3) when smears contain cells consistent with or suspicious for malignancy, biopsy is mandatory.^36,42

 

Chemoprevention

It has been demonstrated that pharmacologic intervention with agents like retinoids will prevent the progression of precancerous lesions to frank carcinoma in primary leukoplakia and in secondary malignancies.^43-48 Although several of the various agents studied in this setting were promising in the single-arm setting, only four (all retinoids) have subsequently been confirmed to be effective in randomized studies.^43-48 13-cis-retinoic acid has been shown to reverse oral leukoplakia, a common premalignant lesion in the mouth.^43-48 There is considerable concern over the toxicity of some particular retinoids used in these trials, and patients receiving certain agents have a dropout rate of up to 10% per year secondary to toxicity.^43-48 Additionally, patients who have previously received chemotherapy and have hepatic disease have been excluded from these trials. There is a reasonably high likelihood that a head-and-neck cancer patient may have either or both of these exclusion criteria. Because the duration of delivery for chemopreventive agents for head-and-neck cancer has not been determined, the use of compounds with unacceptable long-term adverse toxicity profiles is questionable.^43-48

Chemoprevention of oral leukoplakia remains experimental.^48-49 However, because of the high potential of effectively treating oral leukoplakia and epithelial dysplasia, multiple clinical trials are currently underway, including those in the University of Minnesota Preneoplasia Initiative, with several potentially effective chemoprevention agents such as ketorolac, celecoxib, and pioglitozone.

 

Follow-Up

Because many methods of managing leukoplakia are not always feasible or effective, these patients must be observed periodically.¹⁴ The follow-up examination should be frequent (< 6 months) depending on the actual diagnosis and clinical scenario. The follow-up examination includes careful clinical observation and an occasional biopsy.¹⁴ 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 suspicion persists in a lesion that does not disappear, a standard scalpel biopsy must be considered.¹⁴

 

Treatment

Long-term survival and functional results of treatment depend on the stage of the tumor, histology and treatment plan.¹⁴ The treatment plan is developed at pretreatment conferences (tumor boards) by multidisciplinary consultants and subsequent patient/family concurrence. Additional important outcome factors include the patient’s nutritional status, general health, tobacco use, alcohol intake, and anticipated compliance with the rigors of therapy.^50-55

Curative treatment modalities include local surgery with wide margins and radiation or a combination of both. Chemotherapy may be used with these modalities to enhance cure rates and to preserve function, which increasingly has led to organ preservation strategies. If there is a question about the patient’s survival, the choice may be to employ measures to ensure palliation, with pain control and quality of life.^50-55

Head-and-neck surgeons, radiation oncologists, dentists, and rehabilitation specialists all are involved cooperatively in the treatment process. The side effects of treatment are permanent and diminish oral function. Treatment planning is based on careful cancer staging and selection of therapies, which allows for prognostication and facilitates the reporting of outcomes. Physical examination, open biopsy, or fine-needle aspiration biopsy and radiologic imaging studies that include computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are used to classify and stage the disease.^50-55

Most of the major functional disabilities following treatment are related to the volume of the disease, the degree of radiation and/or chemotherapy required for treatment which relates to postoperative complications including: the extent of mandible (or other tissue) loss, reduction of tongue mobility, caries, loss of dentition, xerostomia, muscle trismus, diminished taste and mastication, risk of osteoradionecrosis, and anesthesia of the oral cavity. To achieve a cure, the treatment plan considers an adequate resection of tumor and surrounding normal tissue and the addition of the lymphatic drainage, while attempting to preserve as much normal anatomy and physiology as possible.^50-55

 

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About the Author

Nelson L. Rhodus, DMD, MPH, Morse Distinguished Professor and Director, Division of Oral Medicine, University of Minnesota, Minneapolis, Minnesota