ch02

The exact cause of oral cancer is unknown and mayremain a mystery because of the multifactorialnature of carcinogenesis. Evidence indicates thatalthough inherited genes do influence cancer risk,heredity alone explains only a fraction of all cancers.Mutations of genes and the proteins they producecan alter cell biochemistry and function, causingdisease. On the other hand, alterations of genes(gene therapy) may prevent mutations, control cellgrowth and apoptosis (cell death), and become animportant approach in cancer treatment.

Because time is needed for the cellular eventsinvolved in the development of neoplasia to takeplace, the most prominent associated factor deter-mining susceptibility to cancer is age (see Chapter 1,“Epidemiology”). Variations in incidence ratesamong different groups or populations may be influ-enced by differences in exposure to carcinogenic ini-tiators or promotors. For example, the use of tobaccoor alcohol significantly increases the risk of cancer,indicating an etiologic role. The role of other factorsin promoting human cancer remains important butunclear. For example, immunologic susceptibility,gene mutations, epithelial cell growth, suppressorproteins, and enzyme action all influence cell stabil-ity and health. At a certain time, a cell or group ofcells may undergo uncontrolled growth. This capac-ity for disorderly division continues in daughtercells, and if dysregulation remains uncontrolled, acancer may develop through the production or inac-tivation of proteins, causing local destruction of tis-sues and organs, extensions, and metastasis. In 20generations, 1 cell, with progeny that maintain the

ability to duplicate themselves, becomes the sourceof more than 1 million cells. However, because someof the cells comprising a malignant tumor do notmaintain the ability to divide, and the number ofgenerations varies considerably, growth patterns oftumors are highly irregular and unpredictable.

Humans are exposed continually and simultane-ously to a broad spectrum of biologic agents, chemi-cal substances, and physical forces. To complicatematters even more, each individual reacts somewhatdifferently to these events. As indicated above andfrom the occurrence and demographics of oral andpharyngeal cancer described in Chapter 1, individualreactions differ, conditioned by heredity, age, gender,and a multitude of other modifiers, including lifestylesand behavior. Current evidence suggests one conclu-sion more strongly than any other: there are probablymultiple causes for every type of cancer.

MOLECULAR PROGRESSION

Neoplasms arise clonally from transformed cellsthat have undergone specific genetic alterations inproto-oncogenes or tumor suppressor genes.1 As justone example, loss of chromosomal region 9p21 is acommon genetic change that occurs early in tumorprogression. This leads to an inhibition of cyclin-dependent kinase that is important in cell-cycle reg-ulation. Additionally, a large number of malignantcells express a mutation of the suppressor p53 gene,which, in turn, diminishes cell senescence and indi-rectly promotes growth. Molecular genetics is grad-ually enabling us to unravel some of the critical

7

2

Etiology and Predisposing FactorsSOL SILVERMAN JR., MA, DDSCRAIG S. MILLER, DMD, MS (Viruses)JOAN S. THOMPSON, PHD, RD, CD (Nutrition)

8 ORAL CANCER

events associated with the development of head andneck cancer and precancer.1a Unfortunately, earlygenetic alterations do not necessarily correlate withgross or microscopic changes, which obviously cancomplicate clinical observations and judgments.

As already stated, activation of proto-oncogenesand/or loss of tumor suppressor genes can result inthe stimulation of cell division. As another phe-nomenon, telomeres, composed of repeatingsequences of six nucleotides, are situated at the endof chromosomes. They influence the longevity ofcells and regulate their biologic clock by progres-sive shortening. When activated by telomerase,telomere growth may prevent cell senescence bymaintaining chromosomal integrity. Thus, telo-meres may be a potentially important target in con-trolling cancer. The complexity and multifactorialaspects of explaining neoplasia are evident.

IMMUNE SYSTEM

Immune competence and immune cell surveillancediminish with age. These facts undoubtedly con-tribute to the association between age and malig-nancy. Furthermore, studies have shown that therisks of cancer increase in individuals whoseimmune systems are either congenitally defective orhave been suppressed or altered by disease and/ormedications. For persons in the general populationwho develop oral cancers and who are not otherwiseknown to have or be at risk of immunodeficiency, itis not clear whether differences found in someimmunologic variables cause or result from themalignancy. As our understanding and control of theimmune system progress, a role in prevention andtreatment (immunotherapy) will attain increasingimportance.

TOBACCO

Smoking may be viewed as a worldwide epidemic,causing serious diseases and immense health prob-lems.2 Apart from its effect on mortality, smokingresults in a considerably increased morbidity ratewith consequent losses in working days and produc-tivity, excessive demand on medical services, andincreased health expenditures.3

Tobacco was first introduced to western civiliza-tion by the Spanish explorers of America in the earlysixteenth century. At first, it was simply smoked inpipes, but, as it became more popular, it was alsochewed and snuffed. Cigarettes were first made inSpain in the mid-seventeenth century, and, in thetwentieth century, they became the most popularform of the tobacco habit.

Suspicion of an association between the use oftobacco and oral cancer dates back to the early eight-eenth century, when cancer of the lip was notedamong tobacco users. Several other serious diseases,among them lung cancer, emphysema, bronchitis,laryngeal cancer, and heart disease, affect smokersmore often than nonsmokers. For the heaviest smok-ers, the risks are greatest.

Tobacco Components

More than 4,000 compounds have been identified intobacco smoke. In the combustion mainstream of onecigarette, there are approximately 500 mg of gas(92%) and particulate matter (8%). Eighty-five per-cent of the gaseous phase is composed of carbondioxide, oxygen, and nitrogen. Even though the per-centage of carbon monoxide is low, it raises blood lev-els of this gas significantly, in turn influencing thehemoglobin exchange system. “Tars” (aromatichydrocarbons) range from < 1 mg to 35 mg and con-tain the most potent carcinogens. Nicotine rangesfrom < 1 mg to 3 mg and contributes to habituation,platelet adhesion associated with cardiovascular dis-ease, ulcer susceptibility from decreased pancreaticbicarbonate, and hypertension. Effective filtering canreduce these substances. However, reductions in nico-tine (the habituation factor) and tars (the basis fortobacco’s “taste”) often lead to increased smoking,negating the potential advantage.4 In addition, manyfilters do not filter effectively. Tobacco substitutes (ie,vegetable and wood products) and “smokeless” ciga-rettes have not been popular and have therefore beenfinancial as well as therapeutic failures.

Tobacco Use and Health

Globally, the consequences of tobacco use are stag-gering. By the year 2020, it is estimated that 8.4 mil-

Etiology and Predisposing Factors 9

lion people will die annually from tobacco-relateddiseases, more than two-thirds occurring in develop-ing countries. If current trends continue, more peo-ple will perish annually from tobacco-related illnessthan from any single disease.

Reports from the US surgeon general and othersconclude that cigarette smoking is the main singlecause of cancer mortality in the United States, con-tributing to an estimated 30% of all cancer deathsand substantially to cancers of the head and neck. Afederal law requires that health warnings be printedon all cigarette packages sold in the United States.

Despite intensified warnings about the healthhazards of smoking, American consumption contin-ues at substantial rates, exceeding 600 billion ciga-rettes annually. About 23% of adult Americanssmoke regularly (Table 2–1). The level of schoolinghas an important influence because the prevalenceof smoking is inversely proportional to years of edu-cation. Smoking habits tend to decrease after middleage, most likely owing to medical reasons requiringcessation. There is no question that high taxes havealso been a deterrent.

A recent federal report describing smoking trendsamong American high school students indicated thatin 2001, almost 29% of students in grades 9 through12 were current smokers and 14% were everydaysmokers.4a However, this is a significant decline fromthe 36% rate found in 1997. Smoking frequency wasabout equal between males and females, with only avery slight predominance in boys. There was amarked increase in smoking from ninth graders(24%) to twelfth graders (35%). There were alsoracial differences noted, with the greatest use being inwhites and declining in order from Hispanics, toAsians, to blacks. Whereas the smoking rate in blackadolescents is the lowest among all racial and ethnic

groups in the United States (except American Indi-ans), in adulthood, they have the highest rate. Themost popular form of tobacco use was smoking ciga-rettes, followed by cigars, pipes, and bidis. About 6%of the students had tried a tobacco product by age 11.

Although over 45 million Americans have quitsmoking, the exact magnitude of their lowered riskfor oral cancer is unclear. The percentage of den-tists and physicians who smoke has dropped frommore than 30% to less than 20% during the pasttwo decades.

Oral Cancer Risk and Smoking

The association between cigarette use and oral car-cinoma has been firmly established from epidemio-logic studies, revealing that there are more thantwice as many smokers among oral cancer patientsas among control populations. A study of 403 oraland pharyngeal cancer patients followed for a meanof 5.1 years at the University of California at SanFrancisco (UCSF) found that 72% were smokers and58% smoked more than one pack daily (Table 2–2),demonstrating the very high risk for tobacco users.As discussed in Chapter 1, smoking increases thealready high risk for developing second primary oraland pharyngeal cancers.

Table 2–3 shows, in a follow-up study, thatalmost one of five patients (17.7%) developed sec-ond primary oral/oropharyngeal cancers in a meantime of 5 years. Those who did not change their orig-inal tobacco habits incurred the greatest risk as asecond primary oropharyngeal cancer developed in25.6% of that group. Discontinuing smoking led tothe same rate of second primary oropharyngeal can-cer as in nonsmokers. There was also an increasedrisk for multiple cancers in males, probably becausethey smoked more per day than women and for agreater number of years.

A similar degree of correlation between smokingand second primaries has been reported in otherstudies. One study concerned a group of 203 oraland laryngopharyngeal cancer patients in whom thedisease had been eradicated for more than 3 years.Of 120 patients who continued to smoke, 37%developed second primary cancers, whereas only6% of 81 ex-smokers developed second primaries.

Table 2–1. ADULT SMOKING, UNITED STATES, 2000

Men Women TotalRegion Range % (avr) Range % (avr) Average (%)

Northeast 16–26 (21.7) 16–27 (21.0) 20.8Midwest 17–35 (26.4) 17–28 (22.0) 23.7South 17–32 (25.2) 15–29 (21.0) 23.2West 14–33 (22.4) 12–31 (19.4) 20.6

14–35 (24.0) 12–31 (21.4) 22.7

Adapted from MMWR Morb Mortal Wkly Rep, December 2001.

10 ORAL CANCER

The combined effects of tobacco and alcohol wereillustrated in another study of 351 patients treated fortongue cancer. Forty-three patients abstained fromboth tobacco and alcohol, and 308 were users of oneor both. The abstainers had a mortality of 14% in 5years, whereas the users had a mortality rate of 31%.A second primary cancer occurred in 11% of theabstainers compared with 20% of the users. Obvi-ously, cofactors are critically important.

Numerous laboratory studies have shown thatsome hydrocarbons isolated from tobacco productshave induced buccal carcinomas in animals undercertain experimental conditions. Benzo[a]pyrene,the most potent of these carcinogens, binds to nucleo-proteins and is mutagenic as well as carcinogenic.The association between tobacco use and oral malig-nancies also appears to include cigars, pipes, andsmokeless preparations.

Pipes, Cigars, Snuff, and Smokeless Tobacco

Carcinogenic agents have been isolated from pipe,cigar, and smokeless tobaccos. Although studies ofthese forms of tobacco use have not been as exten-sive as those of cigarettes, the data show a strongassociation between noncigarette forms of tobaccoand mouth cancer. The surgeon general’s report of1964 concluded that “the causal relationship of thesmoking of pipes to the development of cancer ofthe lip appears to be established” (Figures 2–1 and2–2). Fortunately, the incidence of lip cancer hasbeen declining slowly (see Chapter 1).

Whereas the production and consumption of pipetobacco have decreased slightly over the years, therehas been a recent increase in cigars and cigarillos.Regarding cigar smoking in the United States,approximately 5 million cigars are smoked each year,and the use has increased 50% during the past 5 years;women now account for about 5% of all cigar smok-ers.5 Twenty-seven percent of teenagers between 14and 19 years of age have smoked cigars. There are nogovernment regulations on labels, which further com-plicates control. Studies have shown an increased riskfor heart and lung diseases, as well as cancers of themouth, larynx, esophagus, and lungs, in cigar users.An explanation in part is because, in general, cigarshave 7 times greater tar content, contain 4 timesgreater amounts of nicotine, and produce 11 timesgreater amounts of carbon monoxide than do ciga-rettes. Furthermore, cigar wrappings using tobaccoleaf further increase the amounts and dangers of

Table 2–2. TOBACCO USE IN 403 PATIENTS WITH ORAL/PHARYNGEAL CARCINOMAS

Sex (%) Age (yr)Tobacco Users More Than 1

Cancer Site n M F Mean Range (%) Pack/Day (%)

Floor of the mouth 70 59 41 57 (29–76) 94 81Larynx 33 48 52 59 (40–82) 94 79Lip 7 71 29 61 (25–87) 86 43Oropharynx 52 48 52 59 (25–81) 83 63Tongue 142 64 36 55 (25–81) 69 56Buccal mucosa 16 44 56 66 (29–84) 56 50Hard palate 4 25 75 61 (48–77) 50 25Gingiva 34 47 53 55 (43–81) 44 38Nasopharynx 45 71 29 44 (24–71) 42 29Total 403 58 42 56 (24–87) 72 58

Source: University of California at San Francisco.

Table 2–3. SMOKING HABITS AMONG

277 ORAL CANCER PATIENTS

Cancer Smoking Status (n) Status (n)

At Time of 1-Year Second Cancer Post- Primary

Tobacco Diagnosis treatment Oropharyngeal Use (%) (%) Cancer (%)*

Yes 187 (67.5) 90 (48) 23 (25.6)Discontinued 97 (52) 13 (13.4)No† 90 (32.5) 90 (100) 13 (14.4)

Source: Oral Medicine Clinic, University of California at San Francisco, 1989.*Follow-up mean = 5 years.†Never smoked or stopped > 1 year.


these substances. Obviously, the levels of toxic sub-stances vary between brands and with patient smok-ing profiles. Given these variations, some compar-isons between cigarettes and cigars have shown thatthe amount of nicotine and tars in one cigar is equiv-alent to those contained in as much as half a pack toa full pack of cigarettes.

The carcinogenic hazard of snuff dipping andtobacco chewing causes special concern because ofthe marked upswing of smokeless tobacco con-sumption in the United States (Figures 2–3 to 2–8).It has been estimated that over 12 million Ameri-cans (3 million under age 21) use smokelesstobacco.6 Its use among teenagers is increasing andposes a danger for increased oral cancer in thefuture (see Table 2–2). In the southeastern UnitedStates, where women frequently use snuff or chew-

ing tobacco, there is a higher than expected inci-dence of oral cancer in women, together with ahigher mortality. A case-control study in North Car-olina of 255 women with oral and oropharyngealcancer showed an up to 50-fold risk for cancers ofthe gingiva and buccal mucosa in long-term habit-ual snuff dippers. A report on 201 oral cancerpatients at M. D. Anderson Cancer Center in Texasshowed that 46 (23%) used snuff or chewingtobacco. Twenty of these patients reported that, foran average of 44 years, they had consistently heldthe tobacco at the site where the cancer developed.Smokeless tobacco’s influence on carcinogenesisappears to be associated with long-term use, infor-mation that should encourage people in cessationprograms, particularly young athletes. It must bepointed out that there are different risks with differ-ent brands, obviously depending on the ingredients.Reflecting geographic differences, in a recentreport regarding Swedish snuff users, there was noassociation with oral cancer. In summary, though,smokeless (“spit”) tobacco is not a safe substitutefor combustible tobacco products.

Nitrosamines (N-nitrosonornicotine being themost potent) have been identified as noncom-bustible products in snuff and chewing tobacco thatpossess carcinogenic activity.7 Other carcinogens arefound in smaller quantities (hydrocarbons and polo-nium). Interestingly, tobacco products are not regu-lated by the US Food and Drug Administration(FDA), and the nitrosamine levels far exceed thosepermitted in foods (as preservatives). Both sugar andfluoride contents are higher in chewing tobacco thanin other forms of tobacco.8 However, a firm rela-tionship between different tobacco forms and dentalcaries has not been established. On the other hand,many studies have shown an association betweensmoking and periodontal disease.9

Nicotine levels are high and serve as a potent fac-tor in habituation, addiction, and hypertension. Thesalt contained in smokeless tobaccos also con-tributes to high blood pressure. The most commonconditions found with the use of smokeless tobaccoare gingival recession, hyperkeratosis, and staining.Once again, the risk of oral epithelial dysplasia orcarcinoma increases with long-term use of smoke-less tobacco products.

Figures 2–1, 2–2. Relationship between pipe smoking and lipcancer.Figure 2–1. Precancerous leukoplakic lesion at site of chroniccontact with pipe stem.

Figure 2–2. Early squamous cell carcinoma at site where pipestem was habitually held for more than 10 years.

12 ORAL CANCER

Figure 2–5. Patient held tobacco between lower lip and gingiva formore than 5 years, inducing this erythroleukoplakic mucosal lesion.

Figure 2–6. Leukoplakia of the lower labial mucosa at site wherepatient held tobacco during a 27-year habit. Microscopic epithelialdysplasia and intense dental staining occurred.

Figure 2–7. Snuff was held daily buccal to lower right molars for 20years. A biopsy showed verrucous carcinoma.

Figure 2–8. Squamous cell carcinoma at site where snuff was ha-bitually held for more than 30 years.

Figures 2–3 to 2–8. Tissue changes caused by prolonged con-tact with tobacco.Figure 2–3. Gingival recession and loss of attachment are com-mon early changes at sites where smokeless tobacco is held.

Figure 2–4. Patient habitually held tobacco at this site for morethan 5 years.


Smoking and Survival

The hazards of smoking can also be demonstratedby the survival time of oral cancer patients afterdiagnosis and treatment. In a UCSF report of 874patients with intraoral squamous cell carcinoma, the5-year survival rate for nonsmokers was 43%, com-pared with 27% for smokers. In a group of 203 oraland laryngopharyngeal cancer patients studied atanother center, 65% of the nonsmokers were alive atthe end of 13 years, whereas only 30% of the smok-ers survived the same period.

Smoking Cessation

Because tobacco plays such an important role in oralcarcinogenesis, stopping the habit is a fundamental partof prevention and treatment.10,11 Many approacheshave been used, with varying degrees of success.

Fear

Although fear motivates some people to stop smok-ing, in others it may backfire and even increasetobacco use by promoting fear as well as inducingother psychological problems.

Filters

Apparently, as filters become more effective inreducing tar and nicotine, their effectiveness inbreaking the tobacco habit decreases. This findingpoints out the importance of taste and habituation,which are related to tar and nicotine content.

Aversive Conditioning

Methods to make tobacco smoking or taste objec-tionable, such as chemical additives, electric shock,and hypnosis, have not been reproducibly effective.Clinics, organized groups, self-help methods, andmanuals have helped some persons and are pro-moted widely. Studies have not yet convincinglydocumented their long-term value.

“Cold Turkey”

Stopping abruptly rather than gradually has beensuccessful for some patients who are well motivated

and can effectively assign priorities to their lifestyleand goals.

Advertising Regulations and Legislation

These approaches have been ineffective in stemmingthe increasing consumption of tobacco and habitua-tion at an early age. However, taxation and theincreased cost of smoking seem to have some influ-ence in reducing tobacco use.

Counseling

Counseling can be accomplished in brief or intensesessions with individuals or in groups. Leadershipcan involve a variety of professionals with specialtraining in tobacco cessation.

Pharmacotherapy

Nicotine replacement. Because of nicotine habitua-tion and/or addiction, “breaking the habit” may beaccomplished by substituting other sources for nico-tine needs. Probably the most popular have been thetransdermal patches, which yield a stable, fixed dosein decreasing amounts. These patches can be obtainedover the counter without prescription. Gum (Nicorette,2 or 4 mg of nicotine per stick), a nasal spray, andvapor inhalers are other alternatives for nicotinereplacement. Amounts needed vary from patient topatient, and, of course, a patient’s physician should benotified. The nicotine from these sources can irritateoral and pharyngeal mucosae as well as cause otherside effects, such as nausea and dizziness. Also, theylead to rapid peak blood levels followed by irregularand varying concentrations in amount and duration.

Drugs. Some antidepressant medications havebeen useful. The most widely used has been bupro-pion (Zyban) in doses up to 300 mg per day. Bupro-pion has dopaminergic and noradrenergenic proper-ties. There can be many adverse side effects,including xerostomia, irritability, insomnia, andbehavior changes.

Clinical trials involving pharmacotherapy havedemonstrated some limited efficacy—usually a 40to 60% smoking cessation by individuals at the endof treatment but only 25 to 30% at 1-year follow-up

14 ORAL CANCER

(Table 2–4). The best results are seen when pharma-cotherapy and counseling are combined.

Other Carcinogenic Habit Forms

Social customs that can lead to cancer are complexand far-reaching. Some customs, such as betel andtobacco dipping, are widespread and seem to satisfyimportant human cravings. In the areas of the worldwhere these habits are practiced, the incidence oforopharyngeal tumors is comparatively high. Preva-lence varies considerably in different countries,depending on the manner in which the ingredientsare prepared for chewing.

Reports from India reveal that oral carcinomaaccounts for a high percentage of total cancers,ranging from 15 to 65%, with the largest prevalencein the south. A relationship appears to exist betweenthis extremely high occurrence of oral malignancyand the use of various forms and combinations oftobacco, slaked lime, areca nuts, and spices (Figures2–9 to 2–11). In Taiwan, betel (areca nut preparedwith lime) is widely used, resulting in an unusuallyhigh rate of oral cancer, with the main site beingbuccal mucosa (Figure 2–12).

In many areas throughout the world, members oflow socioeconomic groups smoke rolled tobaccoleaves or small cigars with the lit end placed in themouth, termed “reverse smoking” (Figures 2–13 to2–15). In some of these areas, the incidence ofpalatal carcinoma is high.

Precancerous Lesions

Tobacco may clearly induce benign clinical changes ofthe oral mucosa in the form of red and/or white lesions(leukoplakia, erythroplakia, erythroleukoplakia).These changes are considered premalignant because

Table 2–4. SMOKING CESSATION:

GENERAL RESPONSE AFTER 1 YEAR

Counseling (%)

Pharmacotherapy None Brief Full

None 5 10 15Drug/nicotine* 10 20 30

*Bupropion and/or nicotine replacement.

Figures 2–9 to 2–11. Pan habit in India.Figure 2–9. Varying ingredients, including tobacco, areca (betel)nut, lime, and spices, are placed in the betel leaf, which is thenfolded and held in the mouth for prolonged periods of time.

Figure 2–10. Note usual tooth staining resulting from the useof pan.

Figure 2–11. After prolonged pan usage, the risk of squamouscell carcinoma at the habit site increases.


Figures 2–13, 2–14. Reverse smoking habit of many decades’duration.Figure 2–13. Lit end of the cigarillo is held inside the mouth.

Figure 2–14. The palatal leukoplakia is mildly symptomatic. Therisk of dysplastic and malignant changes is moderately high.

Figure 2–12. Areca nut–chewing habit in Taiwan. A, Areca nut pre-pared with lime (calcium hydroxide). The lime increases mucosal ab-sorption of arecoline (a parasympathomimetic agent that has somecarcinogenic properties). B, Long-standing leukoplakia at the site ofholding the nut.

A

B

some may transform into malignancies. Those withcertain clinical features or degrees of epithelial celldysplasia are at greater risk (see Chapter 3, “Leuko-plakia and Erythroplakia”). However, not all oral can-cers are preceded by clinical, precancerous lesions.

Summary

The use of tobacco in all forms—cigarettes, cigars,pipes, chewing preparations, and snuff—increasesthe risk of eventually developing oral carcinoma,which appears to be causally related to this use. Thisassociation is based on the following facts:

1. Carcinogenic agents have been isolated fromtobacco condensates.

2. Tobacco can induce cellular change and tissueatypia.

3. Patients with oral carcinoma use tobacco morethan persons in control groups do.

4. Tobacco used in various forms has been associ-ated with an unusually high prevalence of carci-noma of specific oral sites.

5. Continued smoking is a factor in the develop-ment of multiple oral carcinomas.

6. The mortality ratio from oral carcinoma forsmokers is greater than for nonsmokers.

16 ORAL CANCER

ALCOHOL, CIRRHOSIS, AND CANCER

Death from cirrhosis (primarily owing to alcoholintake) is the eighth leading disease cause of deathin the United States. This high incidence of alco-holism is relevant because alcohol intake has beenrelated to an increased risk of developing oral can-cer and a higher than expected mortality.12,13

More than 35 years ago, a study determined thatheavy alcohol consumption was a significant factorin the development of mouth cancer. In that study,one-third of the 543 male oral cancer patients drankmore than 7 ounces of whiskey per day comparedwith 12% of a control group.

The association between alcoholism and oral andlaryngeal cancer was further affirmed in a studyshowing a large excess mortality (observed-expectedratio more than 3:1) in a group of alcoholics withoropharyngeal carcinoma. In Utah, a state with apopulation approximately two-thirds Mormon, a reli-gious group abstaining from alcohol and tobacco, astudy indicated an incidence of oropharyngeal cancerless than that of the western United States or thenation as a whole.

One group of investigators found that 44% of108 patients with cancer of the tongue and 59% of68 patients with cancer of the floor of the mouth,palate, or tonsillar fossa had unequivocal evidence

of alcoholic cirrhosis. Approximately 75% drankalcohol excessively. In a 1977 study of 408 oral can-cer patients with age-matched controls, Keller con-firmed a previously observed correlation betweencirrhosis of the liver and cancer of the floor of themouth. He found clinically diagnosed cirrhosis in20% of the cases of floor of the mouth carcinoma incontrast to 9% of controls. He concluded that cir-rhosis, heavy drinking, and smoking were associatedwith cancer of the floor of the mouth.

Of 213 evaluable patients studied at the Univer-sity of California, 41 (19%) had laboratory-diagnosed cirrhosis and an additional 26 (12%)demonstrated clinical cirrhotic changes. In the 41patients with diagnosed cirrhosis, 40% had carci-noma of the tongue (only slightly more than the dis-tribution of tongue cancer in the entire group), but46% had floor of the mouth carcinoma (signifi-cantly higher than the rate in the entire group).

The underlying mechanisms for this associationare poorly understood.14 The cause might be relatedto (1) the dehydrating effects of alcohol, renderingthe mucosa more susceptible to carcinogens con-tained in alcoholic beverages (nitrosamines, hydro-carbons), or (2) to liver-induced cellular changes intarget tissues (eg, increased cytoplasmic acetalde-hyde content). Experiments in animals have con-firmed the clinical association between alcoholingestion and tumorigenesis.

Patients with cirrhosis often demonstrate whatappear to be smooth, erythematous, glossy-appearingoral mucosae (atrophic mucous membranes). Inter-estingly, in the past, patients with Plummer-Vinson syndrome (atrophic-appearing oral mucousmembranes, dysphagia, and iron deficiency ane-mia) had a high incidence of carcinoma of thetongue and pharynx.

Most heavy drinkers are also smokers, and thesepredisposing factors probably work in combinationrather than independently.15,16 Several studies con-firm an independent as well as a synergistic rela-tionship between oral cancer and consumption oftobacco and alcohol.

Risk associations between alcohol-containingmouthrinses and the development of oral cancerhave not been established. This was confirmed by apanel convened by the FDA in 1996.

Figure 2–15. Smoker’s palate (nicotinic stomatitis), primarilyseen in pipe smokers. Typical clinical picture includes hyperker-atosis and swollen minor salivary glands with dilated and reddenedorifices (giving the speckled appearance). Malignant transformationis very rare.


SYPHILIS

The rate of syphilis in the United States is decreasing,with currently (2002) slightly over 100 new cases ofprimary syphilis reported each week to the Centersfor Disease Control and Prevention. This rate is lowerthan any previous year but about the same as 2001and almost 30% lower than the occurrence reported in1998. Past reports of patients with oral cancer haveindicated positive histories and/or serologic testsvarying between 6 and 19%. However, little evidencecurrently supports an association between syphilisand oral cancer. Oral syphilitic lesions (chancres andgummas) may clinically resemble carcinoma. Whenany doubt exists in these cases, appropriate serologicand microscopic examinations must be performed.

ORAL LICHEN PLANUS

Oral lichen planus (OLP) is a complex, chronic,inflammatory disease. Mucosa and skin may both beaffected, microscopic features vary, and the orallesions appear in different forms (Figures 2–16 to2–19). The prevalence of OLP is unknown, but it maybe present in as much as 1% of the adult population.

The etiology of OLP is unknown, but it isthought to be an immunopathologic disease. There isno definitive curative treatment, although cortico-steroids are beneficial for control. The oral lesionsare frequently symptomatic and chronic, persistingindefinitely in most patients. OLP is primarily a dis-ease of adults, with the average age of onset about50 years. It is rarely found in persons less than

Figures 2–16 to 2–21. Forms of lichen planus (LP) and associatedcarcinoma.Figure 2–16. Reticular LP, buccal.

Figure 2–17. Erosive LP, buccal.

Figure 2–18. Atrophic LP, buccal, transforming to carcinoma in pos-terior buccal after 13 years.

Figure 2–19. Erosive LP, tongue.

18 ORAL CANCER

30 years old. Women predominate, in a ratio ofabout 2 to 1. OLP can be found in all ethnic groups,with little evidence of familial clustering. AlthoughOLP can occur in any oral site, the buccal mucosa isby far the most common location.

Diagnosis

OLP can usually be recognized by the unique clinicalfeatures of reticular, annular, or punctate keratotic(white) patterns on the mucosal surface.17 The diag-nosis, however, can be confusing because these kera-totic changes may be associated with pseudomem-brane-covered ulcerations and marked erythema.Because many OLP patients are asymptomatic, signsare sometimes recognized unexpectedly during rou-tine oral examination or by chance observation. Themajority of OLP patients do not have skin involve-ment. Diagnosis is confirmed by biopsy.

Malignant Association

Reports have associated OLP with malignant trans-formation (see Figures 2–18, 2–20, and 2–21). Thequestion therefore centers around the magnitude ofrisk and whether it justifies attaching a precancerouslabel to OLP. In two prospective and follow-up stud-ies of 214 and 570 OLP patients at the UCSF OralMedicine Clinic, malignant transformation occurredin 2.5% and 1.2%, respectively.18 Two more recentand independent follow-up studies of an additional

95 and 229 OLP patients in the UCSF Oral MedicineClinic reconfirmed a malignant association.19 Therates of malignant transformation were 3.2% and1.7%, respectively. The mean age of both cohortswas 54, and the mean duration in time after the diag-nosis of OLP to transformation of carcinoma approx-imated 6 years. The prevalence of oral cancer in bothgroups exceeded that expected in a comparable sam-ple of the general population. All of the UCSF stud-ies failed to reveal associations between the develop-ment of carcinoma and gender, smoking, systemicdisease, medications, or site of OLP.

A 1993 report from the United Kingdom, a reviewof 241 OLP patients with associated squamous cellcarcinoma, found that 3.7% developed a carcinomawith a transformation time varying up to 12 years.20 Inthis review of studies performed since 1981, theauthors reported OLP-associated malignancies vary-ing from 0.4 to 5.6% in seven different countries.

It is of interest to compare OLP with leukoplakia(see Chapter 3). The similarities between patientswith OLP and those with leukoplakia include a com-parable age of onset and a hyperkeratotic propensityof the epithelium. Red areas seem to increase therisk for dysplasia and carcinoma in both lesions. Thetwo diseases differ in that OLP seems to be morecommon in women, is primarily inflammatory, andbears no relationship to tobacco use.

In summary, the findings indicate a risk of asso-ciated malignancy in patients with OLP, particularlyin the erosive form and in erythematous areas.

Figure 2–20. Atrophic LP, tongue, transforming to carcinomaafter 3 years.

Figure 2–21. Erosive LP of gingiva, buccal mucosa, and tongue,with development of carcinoma of right lateral tongue after 15 years.


However, a formal classification as a precancerouslesion is reserved until transformation rates can bemore reproducibly established. Therefore, allpatients with OLP should be carefully evaluatedand observed periodically.

DENTURES

Although some carcinomas develop in areas coveredby or adjacent to a prosthetic appliance (Figures2–22 to 2–25), adequate studies have not beendesigned to demonstrate conclusively whether this isa coincidental or a cause-and-effect relationship.More than 35 million Americans over 30 years ofage wear complete upper and/or lower dentures, yetcarcinomas of the palate and alveolar mucosa

together account for less than 14% of all oral can-cers (less than 0.4% of all cancers). However, insome patients, even though the risk is low, irritationin addition to other unidentified factors may possi-bly promote neoplastic activity.

In the UCSF Oral Medicine Clinic, we studied400 patients with oral cancer to evaluate the risk ofwearing dentures.21 Forty-three percent of the groupwore dentures. The study found no correlationbetween the wearing of dentures and any specificcancer site (Table 2–5). Furthermore, denture wear-ers and other patients did not differ in age, gender,time from first signs or symptoms to diagnosis,tumor stage, or tobacco use. Other studies have alsoshown no difference between denture wearers andcontrol groups in the occurrence of oral cancer.

Figure 2–22. Carcinoma developed under a lower denture in an-terior alveolar mucosa after a 15-year history of leukoplakia.

Figure 2–23. Verrucous carcinoma developed under the saddleof a lower partial denture.

Figure 2–24. A carcinoma, at first thought to be an epulis, at thedenture flange of a full upper denture.

Figure 2–25. A carcinoma, at first thought to be a benign kera-totic change stemming from chronic lower-denture flange irritation,involving the anterior floor of mouth and lingual alveolar mucosa.

20 ORAL CANCER

Therefore, at this time, denture irritation does notappear to promote carcinogenesis. However,because chronic denture irritation and oral cancerhave been associated, care should be taken bypatients, as well as dentists, to minimize local irrita-tion and to examine any changes with utmost care.

The same principle may apply to patients whohave poor oral hygiene or jagged teeth or fillingsthat may act as irritants. However, little controlledevidence supports this supposition, although it isfrequently mentioned in articles dealing with the eti-ologic factors of oral cancer. In a few animal exper-iments testing various carcinogenic agents, oraltumor induction has been facilitated by trauma.Denture material per se has not been shown to becarcinogenic.

Placement of jawbone implants with variousmaterials and techniques is increasing at a rapidpace. However, there has been no indication of a car-cinogenic factor (see Chapter 8). But because thesepatients are generally in the higher-risk age group,careful examinations and follow-up, at least, areindicated for coincidental oral tumors.

PALATAL PAPILLARY HYPERPLASIA

Palatal papillary hyperplasia, which is moderatelycommon among denture wearers, consists of grape-like clusters of erythematous tissue on palatalmucosa that is covered by either a plastic or a metalprosthetic appliance (Figure 2–26).22 It is foundmainly in patients who do not have good adapta-tion. Paradoxically, poor adaptation does not nec-

essarily indicate that a subsequent tissue hyperpla-sia will develop. Candidiasis can complicate thediagnosis by producing palatal erythema andsymptoms of burning or pain (Figure 2–27). Themicroscopic picture of palatal papillary hyperpla-sia may sometimes be confusing because thechronic tissue irritation can cause a reactive-typehyperplasia with resultant cellular atypia. There-fore, lack of familiarity with this lesion may lead toan erroneous interpretation of a neoplastic process.Numerous years of observing patients, plus a lackof reports in the literature correlating this lesionwith carcinoma, lead to the conclusion that palatalpapillary hyperplasia is not a premalignant change.

Management demands careful follow-up andelimination of irritation. In case of doubt, biopsy isadvised. Removal of the lesion is elective. However,when indicated for denture adaptation, hygiene pur-poses, or discomfort, many surgical techniques andprosthodontic approaches have been useful to mod-ify the hyperplastic tissue.

NUTRITION

Dietary factors, such as high fat and low fiber, mayplay a role in carcinogenesis in some sites. However,no dietary characteristics have been recognized thatdistinguish patients with cancer of the oral cavity. Inaddition, no body of evidence links oral cancer withdeficiencies or excesses of dietary proteins, fats, orcarbohydrates. Some have suggested that poor den-tal health and denture status might be related to oralcancer risk by causing chewing difficulties that

Table 2–5. COMPARISON OF CANCER SITE AND USE OF DENTURES IN 400 ORAL CANCER PATIENTS

Complete Upper Complete Upper Other Cancers Denture Wearers and Lower or Lower Combinations

Cancer Site (%) (%) (%) (%) (%)

Tongue 34 42 60 30 10Floor of the mouth 23 49 56 27* 17Oropharynx 20 35 54 36 10Gingiva† 10 43 61 28 11Buccal mucosa 6 54 62 23 15Palate 3 43 0 67 33Lip 4 29 75 0 25Total 100 43 56 30 14

Source: University of California at San Francisco.*All upper dentures.†Seven in maxilla.


could adversely affect nutrition. However, no studieshave confirmed this indirect relationship.

Antioxidant Vitamins and Minerals

Deficiencies of antioxidant vitamins and nutrientshave been postulated as cofactors in carcinogenesis.There have been reports of an inverse relationshipbetween ingestion of carotenoids (carotene-rich veg-etables) and cancer risk. More specifically, cancersof the mouth, larynx, and esophagus have beenrelated to low intake of fruits and vegetables. Addi-tionally, active ingredients in fruits and vegetablesthat may act as suppressor agents to control cellgrowth include indoles, flavonoids, isothiocyanates,terpenes, rutin, and phenolic antioxidants. Vegeta-bles are also a source of fiber, which has been asso-ciated with a reduced risk of oral cancer.

Low dietary and/or serum levels of vitamin Ahave been associated with oral precancerous lesionsand subsequent cancer (see Chapter 3). This associa-tion has been based on the correlation between vita-min A deficiencies and hyperkeratosis, as well as ondemographic studies showing high rates of oral can-cer in countries where vitamin A intake is low. Beta-carotene, a weak precursor to vitamin A, is abundantin some fruits and vegetables. Although it is a potentantioxidant (free radical scavenging), beta carotenehas not been effective in the control of premalignantor cancerous oral lesions. However, it must be remem-bered that there are more than 400 carotenoids that

may act as effective antioxidants in the control of cellfree radicals. For example, lycopene, found in toma-toes, has shown effective antioxidant activity in someexperimental systems. Recall that free radicals aremolecules that contain an unpaired set of electrons.These highly unstable molecules are capable of caus-ing mutagenesis and carcinogenesis.23

As for vitamin C, it appears to help block theconversion of nitrites to nitrosamines (potent car-cinogens).24 However, no data indicate that vitaminC deficiencies occur in oral cancer patients or thatvitamin C supplements are helpful in preventing oralmalignancies.

Vitamin E is an antioxidant vitamin that hasaroused much interest. However, no studies haveconfirmed that either a deficiency state increases therisk of oral cancer and precancer or that vitamin Esupplementation reduces the risk.

Minerals have also been studied. Iron deficiencyanemia is part of the Plummer-Vinson syndrome,which has been associated with an increased risk ofdeveloping carcinoma of the tongue. Iron deficiencyhas not been shown to be a common finding inpatients presenting with oral cancer, although highiron storage has been indicated as a possible markeror factor in cancer.25 Zinc and copper also have beenimplicated in head and neck cancer, but one study ofzinc and copper in oropharyngeal cancer patientsfound that serum levels of these elements were notdifferent from those of control subjects and were notuseful as markers.26 Although hypercalcemia indi-

Figure 2–26. Palatal papillary hyperplasia. This usually asymp-tomatic lesion is attributable to a nonspecific tissue reaction to den-tures and is not considered precancerous.

Figure 2–27. Denture stomatitis owing to chronic candidiasis.Thereis little evidence to link candidiasis with carcinoma (see Chapter 3).

22 ORAL CANCER

cates a poor prognosis in patients with head andneck cancer (usually reflecting bone involvement),alterations in calcium metabolism have no cause-and-effect relationship. Some studies have indicateda risk for developing cancer in individuals with lowserum levels of selenium. The role of selenium inhead and neck cancer is unknown.27 Selenium isconsidered an antioxidant mineral that works in con-junction with vitamin E. Selenium is mainly foundin meats, fish, and grains and to lesser degrees indairy products, fruits, and vegetables.

Nutrition is an important factor in the manage-ment of patients during treatment and rehabilitation(see Chapter 7, “Complications of Treatment,” andChapter 8). Poor nutrition and abnormal weight lossare usually associated with cachexia, intercurrentinfections, and a poor prognosis.28 On the other hand,obesity appears to be equally associated with poorsurvival. Obviously, then, factors that encourage ade-quate food intake and a nutritious diet are importantto survival in conjunction with tumor control.29

To reduce the risk factors for oral cancer, a diethigh in fruits and vegetables appears to be prudentand in order.30,31 Dietary Reference Intakes (DRIs)are directed for general health and not targeted forcancer prevention or treatment. Use of large, exces-sive amounts of vitamin supplements may causeimbalances in absorption and function and, therefore,is not necessarily prudent. For example, large amountscould stimulate epithelial growth by diminishing theactivity of cell suppressor proteins (eg, in vitro stud-ies of excess beta carotene serving as a pro-oxidantand altering the function of p53). In general, preven-tion of vitamin and mineral deficiencies is achievedthrough nutritional intake of fruits, vegetables, wholegrains, dairy products, meats, poultry, and fish.When there are difficulties in appetite, mastication,and swallowing, nutritional supplements, includingcalorie-dense foods, are necessary. Nasogastric tubesand gastrostomies may be required in patients withsevere undernutrition (see Chapter 7).

Complementary Medicine

The usefulness of complementary or adjunctive med-icines (“alternative medicine”) is primarily based onnon–evidence-based reports. Although there may be

merit in many nutritional approaches in control ofwellness, some nutritionals (eg, herbs) may havesome adverse side effects and may even be danger-ous (eg, liver damage as reported in the use of kava,an herb taken to alleviate anxiety and insomnia; gin-seng, an herb that affects clotting by interaction withwarfarin; and yellow jessamine, an herb that causesxerostomia). Alternative medicine approaches areoften used in cancer quackery, which often delays thediagnosis and offers improper and inappropriatetreatment to control malignant disease.

The National Cancer Institute has reported that alarge number of cancer patients use herbal medicinesand nutritional supplements to improve their qualityof life. Unfortunately, many patients believe that theyare safe and may even prevent or cure cancer. Asstated above, many of these supplements haveadverse side effects and should be used with cautionand not as substitutes for proven therapies. Oftenpatients do not volunteer that they are using theseagents, which obviously complicates management.

Nutritional Biochemistry

Current areas of nutrition-related research includethe following: (1) enzymatic activity of glutathioneS-transferase and (2) low folic acid status associatedwith elevated homocysteine levels and carcinogene-sis.32 Glutathione S-transferase enzymes are essen-tial for a multitude of chemical detoxification reac-tions, including tobacco carcinogenesis. Geneticmutations that alter these enzymes have shown someassociation with oral squamous cell carcinoma insome studies.

Adequate folic acid levels may be chemopreven-tive. The mechanism appears to involve the inverserelationship between blood folate levels and homo-cysteine, the latter showing an increase in some can-cer patients. Smokers appear to have lower folate andhigher homocysteine levels. Homocysteine is aninflammatory agent to mucosal cells and accumulatesin the blood when folic acid and vitamins B6 and B12

are below normal. The most common sources offolate include fruits, vegetables, and whole grains.Most multiple vitamin preparations provide 400 µg offolic acid (100% of the DRI), which minimizes thecirculating levels of homocysteine.


DENTAL RADIATION

There is no evidence to indicate that exposure toradiation from periodic, routine, diagnostic dentalradiographic examination is mutagenic or carcino-genic.33–35 However, to minimize any potential risk topatients, all procedures that reduce radiation expo-sure (consistent with patients’ diagnostic require-ments) should be used. Years ago, some dentists care-lessly exposed themselves to radiation over a periodof years, leading to carcinomas of their fingers.

FLUORIDATED WATER

In 1977, Dr. Arthur Upton, director of the NationalCancer Institute, made the following statement to theHouse Committee on Government Operations of theUS Congress: “No trends in cancer rates can beascribed to the consumption of water that is artifi-cially or naturally fluoridated.” Numerous studies andcomprehensive reviews that compare mortality databetween communities with fluoridated and nonfluori-dated water document this statement.36,37 Evidence-based studies have not shown that fluoridation posesany hazard to health or an increased risk of cancer.

VIRUSES

The role of viruses in development of oral cancerhas been a matter of speculation for a long time.Although viruses are not known to cause oral squa-mous cell carcinoma, other head and neck cancershave a defined relationship with viruses (Table 2–6).

Of the viruses that infect oral tissues, those havingoncogenic potential are from two groups: the her-pesviruses and the papillomaviruses.

Herpesviruses

Herpesviruses are enveloped viruses containingdouble-stranded deoxyribonucleic acid (DNA)within an icosahedral capsid of 110 to 150 nm indiameter. They cause two types of infections, lyticand latent infection, with periodic reactivation fromthe latent state to cause recurrent and chronic dis-ease. There are eight herpesviruses that infecthuman tissues: herpes simplex virus 1 (HSV-1), her-pes simplex virus 2 (HSV-2), varicella-zoster virus(VZV; human herpesvirus 3 [HHV-3]), Epstein-Barrvirus (EBV; HHV-4), human cytomegalovirus(CMV; HHV-5), and human herpesviruses 6, 7, and8 (HHV-6, HHV-7, HHV-8). Some of these do notrequire consideration in the discussion of oral can-cer. For example, HSV-2 does not normally infectoral tissues, and neither has VZV, CMV, or HHV-7been implicated in oral cancer. The remaining her-pes virus may play some role in oral oncogenesis.

Herpes Simplex Virus 1

HSV-1 is a well-known cause of primary herpeticstomatitis and recurrent herpes labialis (cold sores).More than 90% of the population has been infected.Following the primary infection, the virus remainslatent in the trigeminal or other sensory ganglion forthe remainder of the person’s life and can be reacti-

Table 2–6. VIRUS ASSOCIATIONS WITH HEAD AND NECK CANCER

Association with Virus Genotype Head and Neck Cancer Type of Cancer Association

Human herpesvirus HHV-1 (HSV-1) ? —HHV-2 (HSV-2) No —HHV-3 (VZV) No —HHV-4 (EBV) Yes Hodgkin’s and non-Hodgkin’s lymphomas,

nasopharyngeal carcinomaHHV-5 (CMV) No —HHV-6 Cofactor? LymphomaHHV-7 No —HHV-8 (KSHV) Yes Kaposi’s sarcoma

Human papillomavirus HPV-16, HPV-18 Yes Oral squamous cell carcinoma

CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV = human herpesvirus; HSV = herpes simplex virus; KSHV = Kaposi’s sarcoma herpesvirus;VZV = varicella-zoster virus.

24 ORAL CANCER

vated either to produce recurrent lesions or be shedasymptomatically from infected epithelium into thesaliva. Although the virus is highly cytolytic anddestroys infected cells efficiently, it has the ability totransform cells to a malignant phenotype under cer-tain circumstances.38 This could be important asHSV-1 infection of oral epithelium could, in theory,increase the odds for malignant changes to occur.

If HSV-1 is partially inactivated by exposure toultraviolet light, then it does not kill the cells itinfects. In this experimental situation, the infectedcells can transform to a malignant phenotype. Theybecome immortal in cell culture and will invade andmetastasize if they are injected into an experimentalanimal. The mechanism by which HSV-1 causesmalignant transformation is not known but probablyinvolves mutagenesis. The virus expresses at leastone protein that raises the mutation frequency incells, although the types of mutations, and theirlocation in the chromosomes, appear to be random.

Presumably, an occasional random mutation willoccur in an oncogene, a tumor suppressor gene, or atsome other important site, and the cell that containsthat mutation develops a growth advantage over adja-cent cells and will produce a malignant clone. Simi-larly, a viral infection can cause a cellular mutation orup-regulation of a growth protein. Subsequently, theviral DNA can be lost from the tumor cells (hit andrun), yet the cell continues becoming malignant.Because mutagenesis can also result from environmen-tal or tobacco carcinogens, and many at-risk patientsboth smoke tobacco and shed HSV-1 in the oral cavity,it is difficult to show convincingly that a particulartumor arose because of exposure to HSV-1. However,in vivo experiments have shown that HSV-1 can inter-act with potential oral carcinogens to produce tumors.In the well-known hamster cheek pouch model, HSV-1is co-oncogenic with the tobacco carcinogen benzo[a]-pyrene for the production of oral tumors.39

Epstein-Barr Virus

EBV infects most humans and is best known for caus-ing infectious mononucleosis. It resides latently inlymphocytes and is found frequently in the saliva ofhealthy persons. Experimentally, EBV infection ofhuman lymphocytes can show features of malignancy.

Malignant transformation requires alterations of theapoptotic and growth pathways by the up-regulationof EBV latency membrane protein 1 (LMP1) and thenuclear factor-κB pathway. EBV is associated with anumber of head and neck cancers, including endemicBurkitt’s lymphoma, certain Hodgkin’s lymphomas,and undifferentiated nasopharyngeal carcinoma thatoccurs primarily in Asian countries. EBV can infectoral epithelial cells and is present in hairy leuko-plakia, a benign proliferative condition of the tongue(see Chapter 3). The virus is seldom found in oralcancers. Because oral cancer does not appear to arisein hairy leukoplakia, it seems doubtful that EBVplays any role in the development of oral cancer.

Human Herpesvirus 6

HHV-6 was originally discovered in patients withacquired immune deficiency syndrome (AIDS) andmight play a role in the progression of that diseasebecause it can increase expression of several functionsof the human immunodeficiency virus (HIV). Likeother herpesviruses, it is known to be widespread inthe human population. It causes the mild childhoodinfection roseola (exanthema subitum) and febrileseizures. It is harbored latently in peripheral bloodmononuclear cells, salivary glands, mucosa, and ton-sils and can be reactivated in persons who areimmunosuppressed. HHV-6 DNA has been detectedin biopsies from lymphoma tissue. However, its role inmalignant transformation remains to be defined.HHV-6 proteins have been detected in oral cancercells, and these proteins can transactivate other viruses(eg, HIV, HDV) associated with malignant disease.

Human Herpesvirus 8 (Kaposi’s Sarcoma Herpesvirus)

This most recently discovered human herpesvirus isfound in lesions of AIDS-associated Kaposi’s sar-coma (KS) (see Chapter 12, “Human Immunodefi-ciency Virus–Associated Malignancies”). The factthat HHV-8 DNA is present in KS lesions, a majorityof persons with KS have antibodies to HHV-8, and thevirus can produce lesions similar to KS in experi-mental animals provides strong evidence that HHV-8is the etiologic agent of KS. Recently, the virus has


been identified to infect endothelial cells, and thisinfection, under certain circumstances, results in therecruitment of inflammatory cells.40 The inflamma-tory cells locally produce interleukins and otherchemokines that contribute to the hyperplastic, angio-genic tumor response. KS lesions present commonlyon the face and intraorally (gingival and palate).HHV-8 is not unique to patients with AIDS or KS butis widespread in the healthy population. Immune fac-tors that regulate the recruitment of inflammatorycells may dictate which infected patients develop KS.

Papillomaviruses

Human papillomaviruses (HPVs) are a large groupof related viruses. Over 90 HPVs have been identi-fied. They infect mucosa and skin, causing a varietyof conditions, including warts, condyloma, papil-loma, and cervical and anogenital cancers. HPVs caneither alter epithelial cell growth and replication ordysregulate the cell cycle, resulting in malignantchanges.41,42 Infection outcomes are dependent onthe infecting HPV genotype, anatomic site, andimmune response. Benign or low-risk HPVs (types 6,11, 44, 55) replicate in the lower epidermis and dif-ferentiated cells (keratinocytes), producing increasednumbers of epithelial cells and koliocytosis. Theprincipal high-risk genotypes (HPV-16, -18, -31, -33,-35) are associated with premalignant and malignantepithelial disease, especially cervical cancer.

Two HPV genes, E6 and E7, are expressed contin-uously in infected tumor cells. The function of thesegenes is known and involves blocking the effects oftumor suppressor proteins p53 and Rb. In vitro, cellsthat are transfected with DNA that encodes E6 and E7of HPV-16 or -18 can become malignant.

Cell lines derived from cervical cancer usuallycontain HPV DNA in an episomal or extrachromo-somal form in early passages, but the virus becomesintegrated into the cellular DNA quickly. In oral can-cer, on the other hand, the DNA of HPV is usuallylost after cells have been in culture for a short time.Whether these observations indicate an importantdifference between the role of HPV in the two typesof cancer is unknown. However, a small number oforal cancer cell lines retain HPV DNA sequences,such as the 1483 line. Normal oral keratinocytes can

be transformed to an immortal phenotype by thehigh-risk HPVs, but the cells are not tumorigenic innude mice. They do, however, become tumorigenicif they are exposed to low doses of chemical car-cinogens, a fact that seems to indicate the potentialrole of HPV in the development of oral cancer, alongwith other necessary factors.

HPV has been detected in oral cancer, but theimportance of this finding is not clear. Not all oralcancers contain HPVs. However, HPV is often pre-sent in proliferative verrucous leukoplakia (a prema-lignant oral lesion), and meta-analysis has shown thatthe probability of detecting HPV increases withincreasing dysplastic changes of oral mucosa. Theuse of the most sensitive testing methods has shownthat up to two-thirds of oral cancer cases harbor HPVDNA in their tumor cells. Although the virus is pre-sent in these cancers, at present, the function of HPVDNA in oral cancers has not been fully examined.Many people harbor HPV DNA in oral mucosa, andonly a small percentage of these persons develop oralcancer. HPV-16 and -18 may play a role in the neo-plastic transformation of oral precancerous lesions tomalignancy and are considered by the scientific com-munity as risk factors for oral cancer. Still undeter-mined are important questions regarding the need forscreening of patients who may harbor latent high-riskHPV in oral mucosa and whether HPV-associatedpremalignant and malignant lesions should be man-aged differently from uninfected lesions. Interest-ingly, patients who have HPV-positive head and necksquamous cell carcinomas have improved survivalcompared with patients who have HPV-negative headand neck squamous cell carcinomas.

There are few drugs that will inhibit the growthof HPVs, either in vitro or in vivo. However, ifHPVs could be confirmed to be important in thegrowth of some oral cancers, then several therapeu-tic methods could be useful for the prevention andtreatment of these oral cancers. Immunomodulatingdrugs (eg, imiquimod) applied topically might helpreduce HPV-induced epithelial proliferation. Theribonucleic acid (RNA) transcript from the trans-forming genes of the virus could be used as a targetfor therapy. By inactivating the E6 and/or E7 RNA,E6 and E7 proteins would not be synthesized, andthe cellular tumor suppressor machinery could

26 ORAL CANCER

remain intact. Studies in the 1483 oral cancer cellline have shown that antisense RNA can be directedagainst these transcripts and will slow tumor cellgrowth. An alternative method of inhibition is to useribozymes—antisense RNA with enzymatic activ-ity—to cut HPV RNA molecules. This techniquehas been shown to be effective in cervical cancercells and on the bcl2 oncogene of oral cancer cells.

Another way to exploit active papillomavirusinfections is to use the genetic promoter from thehigh-risk HPVs. If this promoter was used to driveexpression of toxic genes, the construct would killcells in which HPVs are active but not kill othercells. However, these various methods of antipapil-lomavirus therapy remain to be tested in vitro andvalidated in human trials.

VIRUSES IN GENE THERAPY

Although viruses have long been suspected of a rolein the cause of oral cancer, recent research suggeststhat they might be adapted to a role in treatment.43

Gene therapy for cancer is a new research area thatshows much promise and offers several newapproaches to managing cancer.44,45

The thymidine kinase gene of HSV-1 has beenexplored in many laboratories for possible use in

cancer therapy. This gene sensitizes cells to theeffects of antiviral drugs such as acyclovir and gan-ciclovir, which are phosphorylated and made biolog-ically active by the gene product. Therefore, whenthe thymidine kinase gene is introduced to cancercells, without the rest of the virus, the cancer cellsare altered or killed by exposure to specific antiviraldrugs, such as ganciclovir (Figure 2–28). Thisapproach has been shown to be effective in animaltumors, human oral cancer cells in vitro, and humanoral cancers that are transplanted to nude mice. Pre-liminary studies in human oral cancer have begun.

Another possible use for HSV-1 in cancer ther-apy is to use the virus as a vector so that it carriesnew fragments of DNA into a cell and, thus, replacesa missing gene or counters the effects of a defectiveone. Unfortunately, the nonspecific toxic effects ofHSV-1 have limited its use in this way. Several lab-oratories have tried to reduce the cellular toxicity ofthe virus by stripping away the virulence genes. Atheoretical, alternative approach would be to modifythe genome of HSV-1 so that it would grow only inoral cancer cells and not in nonmalignant cells. Sucha virus would kill cancers but not spread to sur-rounding or distant tissues.

Other adenovirus, adeno-associated virus vectorsand retrovirus vectors that can transfer specific frag-

Figure 2–28. Potential use of viruses in gene therapy of oral cancer. The 686-LN oral cancer cell line was exposed to an adenovirus vec-tor, which carries the genes for beta-galactosidase and the herpes simplex gene for thymidine kinase. A, The cells that acquired the genesare stained blue. B, The growth curves show that the thymidine kinase gene sensitizes the cells to the toxic effects of ganciclovir at the lowdose of 5 µg/mL (◆◆). The cells are relatively unaffected by either ganciclovir without the virus (▲▲) or the virus without ganciclovir (■■), whencompared with untreated cancer cells (●●). This suggests that viruses can be modified to provide new forms of gene therapy for oral cancer.

A

1

0.75

0.5

0.25

0

O.D

.560

–O.D

.690

Days Post-Infection

0 1 2 3 4 5 6B


ments of DNA to oral cancer tissues have beendeveloped over the last decade.46–48 These vectorshave less nonspecific toxicity than herpes-basedvectors and can transfer marker genes, toxic genes,or tumor suppressor genes to oral cancer cells.Human trials for some of these approaches havebegun, and data should be available soon.

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