Screening the Non-High Risk Oral Cancer Patient - Part 1
Cancer screening programs: cost and effect questions
In any cancer-screening program it is important to define the population that is to be screened. The population that is defined as having the highest rate of the particular cancer is obviously the most cost effective to scrutinize with the highest number of patients identifies per 1,000 screened. Moreover, the efficiency of the screening will depend on the stringency of the defined risk factors, i.e. the more stringently risk factors are defined; the greater will be the pick-up-rate per 1,000. However, when screening is limited high risk patients, individuals who fall outside these strictly defined risk parameters are not eligible for screening and will therefore be missed.The addition of HPV as a risk factor for oral cancer has made it difficult if not impossible to easily define high risk individuals. OPPORTUNISTIC mass screening is the only viable choice to find oral cancer at precancerous or very early stage high survival stages.
Many professional associations and societies have developed caner-screening guidelines. Accordingly, in spite of differing views, there has evolved agreements on screening guidelines for colorectal, breast, and cervical cancers (1). However, specific guiding principles have yet to be developed for a number of other cancers, especially for populations that lack any persuasive evidence to indicate that a likelihood of high risk exists. This is particularly true for oral cancers particularly in individuals below the age of 40 who are non-smokers and/or non-consumers of alcohol. In part, this has been caused by the recognition that oral cancer is relatively infrequent accounting for only ~ 3 percent of cancers in men and 2 percent cancers in women in the United States.
Oral cancer screening: defining the problem
Oral cancer is an ideal cancer to identify early by screening. It is frequently preceded by an identifiable pre-malignant lesion and the progression from dysplasia occurs over a period of 2,5-8 years. However, published series (2) show that the majority of oral cancers present at an advanced stage (III and IV), when cure rates abysmal. This may be due to the stereotypical oral cancer patient (an elderly male, who abuses tobacco and alcohol) not presenting to health care professionals. Nonetheless, late diagnosis may be related to the fact that an increasing number of oral cancer patients who do not fall into the “high risk” group are not recognized by health care practitioners as being at risk of developing oral cancer. This concept is exemplified by the rise of the female population that is affected by oral cancer. In the 1930’s the male to female ratio for oral cancer was 10:1. With increases in tobacco and alcohol use by women that ratio 2:1 and in our series at the University of Maryland the ratio is 3:2 (unpublished). If screening for oral cancer were restricted to males almost 40% of the cases would be overlooked today, as opposed to only less than 10% of non-diagnosed cases in the 1930’Mw. Interestingly, in this regard there are gender differences between women and men relating to smoking and oral cancer. The relative risk is much higher in women at all levels of smoking (3). Moreover it has also been suggested that women may be more susceptible to cancers that are provoked by alcohol (4).
The two most common approaches of detecting oral cancers are visual inspection and cytology. Neither of these modalities has been shown decrease mortality (5). Consequently, both the United States Preventive Services Task Force (USPSTF) and Canadian Task Force on Preventive Health Care (CTFPHC) have taken a position that although screening can lead to early detection, there is insufficient evidence to recommend for or against routine screening for oral cancer (6, 7). However, both organizations support the principle that educational programs directed toward reducing the use of tobacco and alcohol have merit in sustaining a healthier life. Also the USPSTF recommends a regular dental examination in patients at high risk of oral cancer (7) and the CTFPHC suggests annual examinations by physicians or a dentist to examine for oral cancer in patients older than 60 years with risk factors such as smoking and heavy drinking (6). Based on the fact that the primary risk factors intra-oral (excluding lips) cancer in American men and women is the use of tobacco and alcohol, albeit that infection with HPV-16 and HPV-18 virus has been associated with greater risk of developing squamous cell carcinoma of the oropharynx (8). Despite these recommendations, the National Center for Health Statistics Supplement Survey reported in 1992 that only 14% of the U.S. population has ever had an oral cancer screening (9).
Incidence of oral cancer in young patients: a changing trend
As a result of non collecting population data from screening large populations for oral cancers, little or no attention was initially given to the development of changes in patterns of disease susceptibility. This was especially true for an emergent group of young patients that develop oral cancers, particularly those involving the tongue. Consequently, the increased incidence of tongue cancer was first highlighted by testimonials, letters to the editor, and case reports from Oral Maxillofacial and Head and Neck healthcare professionals. Later, the fact that head and neck cancer, particularly tongue cancer was escalating in young adults in North America, and internationally, began to be recognized from retrospective studies preformed in the late 1980’s (10-16) For example, a review of mortality trends in Europe for a 34-year period from 1955 revealed that a number of countries in Central and Eastern Europe had a 2-fold increase in oral cancer. This increase principally involved males that were under 45 years of age. Similar increases were observed in women in a number of countries (14). In the United States, similar studies preformed during a 20 year period began in the 1960’s revealed that there was a near four-fold increase of oral cancer in males ages 30-39 in the State of Connecticut (16). Likewise, DePue (13) noted earlier that there was an increase in the mortality rates of adults younger than 30 and indicated that these data suggested that this trend began in the mid 1970’s.
Most recently, Schantz and Yu (17) examined the cancer surveillance database from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. These investigators calculated age-adjusted incidence rates for head and neck cancers using a join point regression model, and described tongue cancer incidence trends and established the statistical significance of temporal changes for this disease. These studies revealed that from 1973 to 1997, there were 63,409 head and neck cancer patients in 9 SEER registries. Among this group of patients, 3339 individuals or 5.2%, were noted to be younger than 40 years of age. While the incidence of head and neck cancer remained stable in patients older than 40 years between 1973-1984 compared to the period 1985-1997, tongue cancers in adults younger than 40 years increased almost 60% during the same intervals of time. Notable, was that the estimated annual percentage change occurred until 1985, after which the incidence rate stopped rising but remained increasingly high. In an attempt to define the change more precisely it was discovered that the change in tongue cancer incidence rates for young adults was associated with birth cohorts between 1938 and 1948 and whites but not blacks. These investigators suggested that these populations might have experienced a changing carcinogenic effect on the tongue, distinct from those contained in tobacco. This conclusion was based on the fact that cigarette smoking has markedly decreased among Americans since the 1960’s (18) and among youths in the 1970’s and 1980’s (19). Moreover, the cancer incidence from other systems as well as the upper aerodigestive tract cancers, except for tongue cancer, had declined (20). It should be noted that these changes were not related to any artifact reports biases, since no changes in tumor coding, improved screening programs or diagnostic methods occurred to distort these results (17, 20).
Comparison of survival between high-risk and non-risk groups: new insights
In assessing survival, the literature is replete with studies of small sample sizes that consider survival independent of anatomic location (21). Several authors have reported that younger patients have diminished survival rate from oral cancer (12, 13, 16, 22). In an extensive review Lewellyn et al. (21) noted that it has been suggested by some (23-26) that patients without typical risk factors for developing cancer of the oral cavity may have a worse prognosis compared with patients with usual risk factors of alcohol and tobacco use. Moreover, Kuriakose et al. (27) have suggested that lesions in young individuals were predominantly invasive as compared to exophytic lesions found in older individuals/ Furthermore, when the periods 1973-1984 and 1985-1997 were compared, the d\stage distribution of tongue cancer did not significantly change and that the local-stage disease was approximately 30% to 40% higher for younger individuals than older patients. These findings, however are disparate from those reported by Sarkaria and Harari (26), which demonstrated that 64% of young patients had Stage I and Stage II disease at presentation. More importantly, Davidson’s review (28) of SEER database showed that disease specific morality from tongue cancer increases with age. It may be that this is a reflection of increasing co-morbidities in order patients, which have been shown to adversely affect head and neck squamous cell carcinoma survival (28).
Shantz and Yu (17) found that from 1973 to 1997, 5-year survival rates for tongue cancer increased in all age groups. The absolute increase in survival was greatest in Americans younger than 40 years. Also, survival improvements was more pronounced in young patients that were male, white and at an advanced tumor stage, while survival rates were found to diminish in young non-white patients. There was a greater than 20% survival improvement in young patients with regional or distant stage disease compared to earlier periods. This may be attributed early intervention was selective neck dissections in N0 (non-affected) necks of tongue cancer patients are opposed to the previous “watch and wait” approach. However, the absolute increase in survival was 3% in young patients with localized disease. During these periods there were comparable increases in the survival rates for older individuals when analyzed by sex, race and stages, with the exception of black populations aged 40 to 64, in which a decrease survival rate was observed (17).
Etiologic factors: possible explanations for changing profile in oral cancer.
The temporal and age dependent changes seen with the increase in incidence of oral cancer and specifically tongue cancer have implied the possibility of a changing carcinogen effect on the tongue, particularly distinct from those contained within tobacco (17). A number of etiologies have been proposed as possible explanations for this changing profile of oral cancer.
Although much attention has focused on young patients who are non- smokers (29, 30), non-smokers at all ages can develop oral cancer. Koch et al. (31) found a disproportionate number of females, oral cavity cancers (particularly tongue), and very young and very old patients. In the Maryland experience 99 of the 500 consecutive oral cancers (20%) were found in non-smokers. In this series 60% were females; tongue and gingival accounted for 75% of all sites with only 3% floor mouth cancers. Patients below 40 and above 70 were increased compared to the general group. There was an increase of premalignant lesions particularly white patches in the non-smokers. Interestingly the incidence of second upper aerodigestive tract cancers was the same for non-smokers as smokers (13%). Virtually all-second primaries in non-smokers occurred in the mouth (unpublished data). Koch et al. confirmed a low rate of p53 mutations loss of hetrozygosity, and chromosomal mutations in the non-smokers group. HPV viruses were no different between smokers and non-smokers. He postulated a separate mechanism for carcinogensis in group possibly involving p16. However, no etiology for the development of cancer in this group is known (32).
Alcohol is an independent risk factor for oral cancer (4, 33), and has been cited as the most important risk factor in non-smokers. However, many non-smokers are also non-drinkers, in fact, 50% of our non-smokers never drank and 37% drank less than one alcoholic beverage a day. Although reports have implicated mouthwash use in these patients, a review of seven cases controlled studies on mouthwash and oral cancer failed to show and link (34). Binge drinking of alcohol has become more prevalent with some American youth; however, the duration of exposure appears to fall short of the time required for malignant transformation to occur. Moreover, drinking among Americans in general decreased from the 1930’s to the 1990’s (17, 35). In comparison with Americans, studies reported from India (36) and more recently from the United Kingdom (UK) indicated that risk factors of tobacco use and alcohol consumption were present in the majority (75%) of patients below the age of 45 years (37). Significant differences in the pattern of alcohol consumption were found in female subjects, who were less likely to consume over the recommended amounts of alcohol compared to the male subjects. Interestingly, daily regular fruit and vegetable consumption during the ten-year period before cancer diagnosis was recorded to be low. However, there was a distinct subgroup of cases, 26%, which had little or no exposure to any major risk factors (37).
Among Americans another factor that has been recently advocated as causative for developing cancer has been the use of smokeless tobacco; such agents have been implied in the development of precancerous leukoplakia (16, 38-41). However, in spite of the increased popularity of the use of this form of tobacco, the regional differences in use of these products within the Americas, and Europe, and the fact that American women have shown significant increases in tongue cancer with a low rate of smokeless tobacco use (0.3%) raises doubt as to the significance of these products in accounting for this form of tongue cancer. Intriguingly, West Virginia has highest use of smokeless tobacco and a lower than average rate of oral cancer. Moreover, the incidence of non-tongue oral cancer (cheek and gingival), an area that is used to harbor smokeless tobacco, has remained constant in the United States and the United Kingdom (10, 42).
The reports by Zhang et al. (43) of a does dependent association between the use of marijuana and head and neck cancer risk, particularly in young patients, has raised the possibility as to the role that such habits may have in causing cancer. It has been estimated that 31% of the population of the United States 12 years and older in 1992 have ever used marijuana. The incidence of marijuana use sharply increased in the United States, in male and female teenagers, and young adults in the 1960’s corresponding to the cohort born between 1941 and 1955 (44-46). Such timing would seem to correlate with the increased expression of tongue cancers. Additionally, there exists laboratory and experimental evidence to suggest that there is a carcinogenic effect of marijuana. Correlative human studies verifying this association with oral cancer have yet to be preformed. Moreover, it should be realized that the use of marijuana was not a 20 th century novelty only indigenous to the youth of Central Europe, and the Americas, and the patterns of oral disease in other populations have not mirrored the findings being addressed here. In fact, a comprehensive review of the association of marijuana and squamous cell carcinoma of the head and neck in 2002 concluded that more evidence was necessary to prove marijuana’s link to head and neck cancer (47).
Another consideration that has been raised to account for the increased prevalence of tongue in young individuals has been in the association between various genetic polymorphisms and susceptibility to develop oral squamous carcinoma (30). In fact, a number of studies have established that low does exposure to tobacco increases the risk for the development of oral cancer in individuals with GTS1 and CYP1A1 polymorphisms (48-50). However, the low frequency of such genetic alterations within the population cannot account for the increased rate in tongue cancers. Some have suggested that familial clustering of cancer points to a genetic component in the development of squamous carcinoma at a younger age (21), however; no studies in the offing have provided clear-cut evidence to date to support this view.
The role of viruses in the etiology of oral cancer and particularly the evolving subset of young patients without risk factors that develop tongue cancer has likewise proven to be unconvincing. Although Epstein-Barr virus (EBV) has been implicated in the development of lymphomas, and nasopharyngeal carcinomas, the influence of EBV in emergent oral squamous carcinomas is unresolved. Van Heerden et al. (51) reported that EBV DNA could be identified with near equal frequency in patients harboring SCC that were over the age of 40 years as well as patients less then 40 years of age and control patients with non-neoplastic oral conditions. As such, these investigators were able to conclude that EBV did not distinguish the development of cancer in patients based on age.
The role of human papilloma virus (HPV) in the development of oral cancer is likewise fraught with contradictions. Although oral sex has been suggested to be more common in young people and potential source of oral colonization of HPV, these conclusions may be misleading, as such practices have rarely been studied in defined populations. Recent reports (52-54) have shown that a subset of patients that develop oropharyngeal squamous carcinoma have been shown to be less apt to use alcohol and tobacco rather exhibiting a strong correlation with HPV-16. Also, the presence of HPV appears to confer a survival advantage among head and neck squamous carcinoma patients, particularly when p53 is wild type (55). However, these patients do not account for increases in incidence in tongue cancers reported over the last decades (56).
Future directions: dealing with the problem
The increasing incidence of SCC of the oral cavity particularly tongue cancers, among younger individuals and the evidence that traditional risk factors may not be responsible for this change in disease, raise concern for the need for more definitive and cost effective means to detect SCC in what has been traditionally considered low risk populations.
The development of effective visualizing systems and less invasive cost effective sampling methods should help temper the public health concerns regarding the justification for prudent screening of such populations. At the same time, the assessment to risk needs to be further developed by determining the profiles of molecular alterations seen in young tongue cancer patients. For example, Lingen et al (29) showed that 81% of young patients with tongue cancers over expressed p53 by immunohistochemical analysis. Furthermore, none of these patients demonstrated mutations in exons 5-6, which are known to be “hot-spots” for the gene alterations in conventional oral cancer. Thus, suggesting that young individuals with no risk factors had altered p53 function in oral squamous cell carcinoma that differed from those of more typical population of individuals that develop this malignancy. Unfortunately, this paper and others (57) examined only young patients who were non-smokers/drinkers, confounding the results with 2 variables. It is known that non-smokers have only 14-17% p53 mutations (58) compared to 40-50% in smokers (59). Moreover Atula’s study of 34 young patients many of whom were smokers and drinkers found are 51% in advance p53 mutations (60). Similarly, the expression of chromosome g\fragility following the use of marijuana in such populations might prove informative as young adult populations with SCC have shown to express significantly increased numbers of bleomychin-included chromosome breaks (61).
Recently Mendez et al. (62) using oligonucleotide arrays that contained probes representing approximately 7000 full-length human genes and hierarchical clustering analysis, showed that oral carcinomas are distinguishable from normal oral tissue based on genome-wide transcriptional expression. Recognizing that patients diagnosed with SCC at a young age show evidence of genetic instabilities as well as variant patterns of alteration of the tumor suppressor gene p53, raises expectations that the development of DNA and proteomics chip arrays might well define some of the underlying factors for the development and progression of SCC at a younger age. Such pioneering approaches are likely to have an extraordinary impact on cancer biology, and provide opportunities to unravel the thus far unidentified mechanisms involved in squamous cell carcinogenesis. They are also expected to provide a molecular blueprint for head and neck squamous carcinoma. This will also help to discover appropriate markers for the early recognition of precancerous lesions, and identify novel targets for intervention in this disease.
Salivary diagnostics are showing progress as a vehicle for mass screenings of large populations. Samples maybe taken by auxiliary staff, analyzed by computer analysis and results returned in an expedient manner.
Robert A. Ord 1.2, Nikolaos G. Nikitakis 3, and John J. Sauk 2.3
1 Department of Oral and Maxillofacial Surgery
2 Department of Diagnostic Sciences and Pathology
3 Greenebaum Cancer Center
University of Maryland, Baltimore Dental School, Baltimore Maryland