Portuguese Version

Year:  2004  Vol. 70   Ed. 5 - (15º)

Artigo de Revisão

Pages: 679 to 686

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Squamous cell carcinoma of the oral cavity in young patients and its increasing incidence: literature review

Author(s): Beatriz R. M. Venturi1,
Ana C. F. Pamplona2,
Abel S. Cardoso3

Keywords: carcinoma, oral cavity, young patients.

Abstract:
The purpose of this study was to review the squamous cell carcinoma of the oral cavity in young population. The literature shows a different behavior in this type of disease; it seems to be more aggressive. There is a close relationship between some habits (tobacco and alcohol consumption) and the development of squamous cell carcinoma of the oral cavity, but in this case the patients normally relate no risk factors. There is a little number of case report of squamous cell carcinoma of the oral cavity in patients under 40 years old, so it's difficult to prove the increasing of the squamous cell carcinoma of the oral cavity as said in the literature. Further studies are necessary to know better this entity. The identification of the characteristics of this young population is necessary, because it might reflect problems in cancer control and can enable the development of a primary prevention program for squamous cell carcinoma of the oral cavity in young patients.

INTRODUCTION

Oral cavity and oropharynx cancer represents approximately 3% of all malignant damages in men and 2% in women in the USA 1. According to the types of cancer that affect the oral cavity and oropharynx, 90% of them are squamous cell carcinoma (SCC)1. It is normally found in male patients, aged between the 5th and 8th decades of life, and it is rare among people aged below 45 years 1.

Histologically, malignant epithelial cells appear on the superficial epithelial layer, which proved to be different from other squamous cells of the normal epithelium; they have an invasive behavior towards the underlying connective tissue 1. The fact that this type of cancer is not common in young patients makes the knowledge about etiological factors, better treatment and prognosis to be very limited 1.

Oral cavity SCC can clinically take on different aspects in its initial stages, presenting as a leukoplastic, erythroplastic, leukoerythroplastic lesion or ulcers that frequently do not heal 1.

Currently, there are 50,000 new cases of head and neck SCC in the USA and over 500,000 in the world 2. In Brazil, estimates of incidence rates of oral cancer reported by INCA in 2002 were 8,340 cases in men and 2,915 cases in women, with 2,715 deaths of men and 700 deaths of women 3. In Rio de Janeiro, they estimated 1,410 cases of oral cancer in men and 530 in women, with 420 deaths of men and 100 deaths of women 3.

Scientific literature has recently given more attention to SCC of tongue in young adults, which used to be considered a clinical entity distinct from squamous cell carcinoma in adults (1975) 2, 4-12, given that head and neck SCC in young adults were uncommon, representing only 0.4% to 4.8% of all tumors that occurred in patients aged over 40 years 2.

A review of the American literature revealed fewer than 200 reported cases of tongue SCC in patients aged less than 40 years 2. In fact, there are few publications about treatment and effects of this disease because of its rarity 5.

It has been suggested that oral SCC in young patients may be a different disease from that that occurs in elderly patients, with specific etiology and clinical progression 8, 13.

Together with increase in incidence, there is lack of knowledge about survival rate of affected patients. Traditional risk factors may be responsible for the incidence of oral cancer cases in young patients, which demonstrates the need for better understanding the epidemiology of oral cancer.2,5,6,8-10,13-15

Literature reports concerning risk factors, such as alcohol and tobacco use, for oral SCC are vast and widely recognized 1. However, many authors have reported that already known risk factors, such as smoking and frequent intake of alcohol, which are considered important factors in cancer cases of elderly patients, may not be as important in young cancer cases, showing that there might be differences between risk factors for young and older patients. In addition, even if risk factors had been present in young people, they would have been exposed to them for shorter periods of time if compared to elderly patients 2,6,8,9,13.

The purpose of the present study was to conduct a literature review about the topic to analyze incidence of oral cavity SCC among young adults, gathering different studies, given that isolated samples tend to be small. It also aimed at addressing the association of risk factors and the prognosis of SCC in the oral cavity of young people, emphasizing early diagnosis.

LITERATURE REVIEW

In American medical literature, there is variation of incidence of oral SCC in young adults of 0.9% to 10.3%, and these data differ from one center to another 14. In private institutions, 4% of cancer cases affect young people, whereas this occurrence is 10.3% in public hospitals 14. In public hospitals there is higher prevalence of African-descendents, whose prevalence is 6.6% against 2.9% in Caucasians 14.

Oropharynx and oral cavity cancer in young adults is a rare entity presenting an incidence of 2.7% out of a total of 1,014 patients seen or treated in the Department of Therapeutic Radiology of Yale - - New Haven Medical Center between 1958 and 1980.15

Many studies have suggested that head and neck cancer, especially of the tongue, is increasing internationally in young adults 2,5,6,8,9,13 . In the USA, there has been increased mortality rate of tongue cancer in young adults aged less than 30 years from the 70's 10. In Connecticut, USA, there was 4% increase in oral cancer in men aged 30 to 39 years between the 60's and the 80's 10. In Houston, Texas, USA, the rate increase from 4% in 1971 to 18% in 199310.

A study involving 24 European countries demonstrated increase in rate of oral cancer between 1955 and 1989; 10 countries demonstrated increase greater than two percentage points in men aged less than 44 years and three countries showed similar increase in women 10. The countries that presented this increase are especially those in Central Europe, including Austria, Germany, Hungary, Poland and Bulgary.10 Studies conducted in England have also reported that there is an increasing number of oral SCC cases in young adults, especially tongue cases 13.

In Finland, there is a growing rate of tongue SCC in young adults: 3% increase between 1953 and 1962 and 7% between 1983 and 1992.6

In India, oral carcinoma in patients aged less than 35 years represents 2.8% of all cases of oral cancer in the reference center, whereas it represents 0.4 to 5% in the north region.8

In Martin-Granizo et al. (1997) study, out of a total of 294 patients with oral SCC confirmed by biopsy, 8.2% are aged 40 years or less, and 20.8% were younger than 30 years 14.

Verschuur et al. (1999) analyzing patients with less than 40 years reported that they represented 1.84% of 10,072 cases of oral SCC.16 This series did not demonstrate increase in rate of oral SCC in young patients between 1958 and 1992.16

Despite rarity of oral SCC in patients aged less than 45 years, most rates ranged from 0.24 to 9.0%; Hart et al. (1999) showed a rate of 15.75% for this type of tumor.17 However, this high percentage can be in part explained by the small number of studied subjects and by the fact that military activity is more common among young people, given that they included military personnel in their study 17.

In an extensive literature review, Bill et al. (2001) reported that patients aged less than 40 years represent only 2.7% of the total number of patients that present oropharynx and oral cavity cancer 18. The same authors observed that the tongue and lower lip are the most common sites of affection in primary SCC 18.

Schantz and Yu (2002), based on the records of the National Cancer Institute of the division of cancer control and population sciences, that covers about 10% of the American population, analyzed between 1973 and 1997 63,409 patients with head and neck cancer, and 3,339 were aged less than 40 years.10 Tongue cancer in young American people has shown an increase of 62% when compared to the periods of 1985-1997 and 1973-1984.10 Differently from tongue cancer, the incidence of other cancer cases in young American people, including pharynx and larynx cancer, has remained relatively stable during the same period.10

As to site of SCC affection in the head and neck of young adults, oral cavity and oropharynx lesions are the most frequent ones, followed by laryngeal lesions in the study by Lipkin et al. (1985) with 39 cases of head and neck SCC in patients aged 40 years or less 19. However, there can be increase in incidence of oral carcinoma of tongue in young adults, which was 5.3% in 1950 and 7.2% in 1980, and the peak was 8.6% in 1970.6 Confirming this increase reported in the literature, Lype et al. (2001) reported that tongue was the most common site, affected in 52% of the cases, followed by jugal mucosa in 26%, demonstrating predominance of intrabuccal sites.8

As to proportion of men and women affected by SCC, men seemed to be more affected than women in variable ratios, from 1.3:1 to 2.1:1.10,14,15 However, higher values in women have also been found in ratios that ranged from 0.9:1 to 1:2.3.8,10,14,15

In a study with 10,072 patients conducted by Verschuur et al. (1999), 69% of the cases were in women.16

A careful analysis of Koch et al. (1999), comparing smokers and non-smokers, confirmed and strengthened many observations already made in the literature: most non-smokers with head and neck SCC in the study were men.20 Most women in the group were smokers.20

Risk factors (tobacco, alcohol, p53, genetics)

Alcohol and tobacco

Inhalation of tobacco plays a carcinogenic effect on the larynx and lungs. The habit of chewing tobacco makes it dissolve the saliva and produces cancer of the mouth floor, tongue, and retromolar region; alcohol is predominantly a co-factor of tobacco, increasing the risk of SCC of the oropharynx and esophagus 14. It is known that tobacco increases 7 times the risk of oral SCC onset in the population in general, and if associated with alcohol, the risk increases to up 15 times 12.

The use of tobacco, particularly among men, seems to be less common in young age range that has higher incidence of cancer 21. Moreover, lung cancer has also shown strong decline in this population group 21. However, in the sample by Mackenzie et al. (2000), in which 109 patients aged less than 40 years were analyzed between 1981 and 1995, it was shown that most of them (68%) stated that they were regular smokers, among which, 58% have used tobacco since the age of 15 years or less 21. Conversely, recent evidence has suggested an increase in incidence of oral SCC in subjects that use tobacco and alcohol chronically 2. Increase in incidence of tongue SCC is observed in patients aged less than 40 years, who do not present risk factors 2.

Based on such facts, there are currently major controversies about the role of traditional risk factors, such as alcohol abuse and tobacco, in the etiology of SCC in young adults, given that studies demonstrated an association between them 17, 19, whereas others did not find any correlation 2,7,16,20. We tried to promote a chronologic report to better understand the facts.

In the study by Byers et al. (1975), 11 patients aged less than 30 years with tongue SCC stated that most of the regular risk factors, such as excessive smoking, alcohol abuse and poor oral hygiene, were not present.7

Lipkin et al. (1985) reported that mean age of patients with SCC is about 36.3 years and they were almost all smokers and heavy drinkers 19.

According to Cusumano and Persky (1988) oral cavity carcinoma occurs more frequently among women aged less than 35 years who are not submitted to risk factors such as tobacco and alcohol 22. This fact suggests that other risk factors are associated with oral carcinoma presented in young women 22.

Koch et al. (1999), comparing non-smokers with smokers more commonly observed the presence of laryngeal and hypopharyngeal tumors in smokers; non-smokers normally presented intra-oral tumors, were female subjects and with extremes of age, either too young or too elderly 20. In the group of smokers, there was mutation of p53 protein 20. The rate of infection by HPV was slightly increased in the non-smoker groups 20. Former smokers presented molecular characteristics similar to that of non-smokers 20. They also demonstrated that there was no association between age, smoking history and survival from head and neck cancer, but they suggested that the spectrum of mutations differ for smokers and non-smokers' cancers, regardless of age or head and neck site 20.

According to Verschuur et al. (1999), there is less alcohol consumption among young patients 16. Out of patients aged over 40 years, 35.1% do not report alcohol use, whereas 57.3% of young patients report they do not drink alcohol 16. Differently from what the literature brings, the number of non-smoking patients with oral SCC separated by age was not statistically significant 16. Analyzing smoking, 8.3% of patients older than 40 years were non-smokers, whereas 34.1% of young patients were non-smokers 16. Even though some patients in the group of young patients drink alcohol, none of them who are aged less than 30 years have done it excessively or for a long time 16. Other factors, which include smoking marijuana, chewing tobacco, alcohol-based mouth washer, passive exposure to tobacco or genetic predisposition to development of head and neck, they could not be defined in the present study 16.

Differently from other reports, Hart et al. (1999) demonstrated strong association between tobacco and, less frequently, alcohol consumption and development of oral SCC in young people, reporting use of tobacco in 77% of the population in the study 17.

Lingen et al. (2000) examined 21 patients and none had previous history of marijuana or tobacco use, but 14 stated they had drunk socially 2. None presented history of exposure to radiation, increased risk to a specific type of cancer or history of family predisposition, as well as considerable occupational or environmental risks 2.

In the study by Lype et al. (2001), half of the 264 patients aged less than 35 years with oral cancer were alcohol abusers or smokers, compared to 99% found in patients over the age of 35 years 8. Thus, they suggested that the lesion should be investigated even if the patient is not associated with risk factors, given that approximately 40% of the patients in the study did not have history of contact with known etiological factors, emphasizing the importance of early diagnosis in this type of lesion.8

Association of Factors

The process of oncogenesis in young adults can be completely different from that in elderly patients 20. There may be a genetic predisposition for head and neck SCC that has not been identified, for example, in a received gene or a defect in DNA repair, causing predisposition to the development of mutations, such as in known oncogenes, such as p53 and others 20.

Can tongue cancer in young patients be considered a distinct disease? Immunohistochemical studies to detect p53, p21 protein Rb and MDM2 in tongue margin cancer lesions in 36 patients aged less than 35 years and to a similar number of patients aged over 75 years did not support this statement 22. Some studies demonstrated that there are no differences between p53 in both groups 6, 22, even though there is a reference that p53 mutations are more common in tongue cancer cases in young patients without previous history of alcohol and tobacco use 6.

Lingen et al. (2000) reported detection of p53 in 81% of young adults with oral carcinoma2. Twenty-two patients aged less than 40 years were studied between 1986 and 1996 and two presented overexpression of p53 and very aggressive tumors, which led to death within two years after initial diagnosis 2. Genetic defects in smokers can have an important role in the etiology of oral SCC 24. Etiology is also uncertain, but it has gained continuous importance.24

A future consideration for the development of head and neck SCC in young adults can be genetic predisposition to environmental carcinogenic agents, chromosome abnormalities, increase in susceptibility to chromosome damage induced by mutagen or deficient DNA repair.16 Other causes proposed for oral SCC in young patients without risk factors in addition to immunosuppression are viral infection, hereditary factors, xeroderma pigmentosum, or oral exposure to chloride polyvinyl. 2

The occurrence of oral SCC in children is rare, and most cases found association with systemic diseases, such as for example epidermolysis bullosa, xeroderma pigmentosum, and juvenile papillomatosis. 18

Prognosis (aggressive behavior, prognosis, survival)

Owing to the small number of cases of oral SCC in young patients, many facts are still discussed: rates of incidence, related risk factors and, over all, tumor behavior 24. Authors are divided concerning prognosis and behavior of cases, and we decided to conduct a chronological review to better understand viewpoints discussed in the literature.

In a sample of 64 patients aged less than 40 years and followed up between 1973 and 1995, divided by age in older and younger than 30 years, young patients presented better prognosis. However, this difference was not statistically significant 4.

According to Lipkin et al. (1985), development of SCC in early age can be related with heavy alcohol abusers and smokers, and low survival is owed to negligence and patients' fault, who do not look for medical support in initial stages of the disease.19

Son and Kapp (1985) reported that out of 1,014 patients studied in Yale between 1958 and 1980, in which 2.7% were young adults, three-year survival was observed in only 17%.15

Despite the fact that most studies report poor prognosis, the study with case control did not show significant differences in recurrence or survival rates.16

Sarkaria and Harari (1994) reported high local-regional recurrence rate as well as high mortality related to disease in the young group of patients in a study with 152 cases of oral carcinoma in patients aged less than 40 years, in which 47% died 9,24. These authors did not consider that oral SCC in young patients is very aggressive or had worse prognosis.9,24

According to the observations by Martin-Granizo et al. (1997), there is development of recurrence in 6% within the first 18 months, but none of them occurred in the period between 1.5 year and 5 years of follow-up 15. The authors also stated that there are no statistically significant differences in survival rates in men and women, even though poorer prognosis can be observed in the male group 14.To these authors, it was not possible to assume that oral cavity SCC has a more aggressive behavior in patients aged less than 40 years 14.

Cusumano and Persky (1998) demonstrated worse prognosis in women aged less than 35 years with oral SCC and they reported that Byers7 emphasized a more anaplastic pattern (poorly differentiated) of oral SCC in young adults, resulting in poor prognosis.7,15,22

Studies by Siegelman-Danieli et al. (1998) did not show differences in survival of patients with tongue cancer and age, but they reported a tendency towards poor survival in patients without history of alcohol use and smoking.11

Differently from many studies in the literature, Jones et al. (1998) studied 2,647 patients and demonstrated higher survival rate in young patients 25. Five-year survival rate in patients with SCC of the head and neck from the third to the seventh decades of life reached 54% and between 8th and 10th decades it was 44%; this difference was statistically significant 25. Patients aged over 80 years presented greater severity of disease in the primary site, but surprisingly, they had less lymph node metastasis than younger patients.25 As to type of treatment chosen, young patients are normally treated with radical surgery, whereas patients over 80 years are not treated radically 25. However, choice for radical radiation was similar in both groups 25.

After the study by Schantz in 1988, reported above, Verschuur et al. (1999) used 185 patients aged less than 40 years and 185 aged over 40 16. The results demonstrated that there was no difference in prognosis of SCC in young people 16. However, older patients demonstrated that they were more prone to developing second primary cancer, such as for example, head and neck, lung or esophagus tumor, probably secondary to cancer transformation of the field caused by smoking 16. When compared to groups of non-smokers, younger patients presented longer 5-year survival 16. The results of this study suggest that prognosis in younger patients with oral head and neck SCC is not worse than in older patients.16

To Hart et al. (1999), survival rate of young patients is similar to that of patients with oral and oropharynx SCC and it was also similar in all stages of the lesion 17.

In the study by Vargas et al. (2000), women aged less than 40 years with oral SCC of the tongue presented local recurrence rates higher than those observed in the groups of older patients with the same disease 12. These patients have shorter disease-free interval before they have a recurrence when compared to the other group 12. Even though survival rate was not significantly different between both groups, it was observed that young women with oral SCC tended to have shorter survival 12. However, many different studies, especially the most recent ones, have shown that young patients with oral SCC do not have worse prognosis.8,23 Moreover, 5-year survival rate in young adults was 77.7% to Myers et al. (2000), comparable to survival rates reported by retrospective studies with patients of tongue cancer of all ages.4

Davidson et al. (2001) did not report statistically significant differences in clinical progression or prognosis of tongue cancer in patients aged less than 40 years, even though the control group for such a comparison had not been described 23. Even though there was no difference in survival, despite extensive use of radiotherapy in young patients, local-regional recurrence was significantly more common in these patients.23 Patients did not present differences in survival and age, but there was higher survival in patients with previous history of alcohol and tobacco use 23.

Despite the report of some authors about anaplasia of tumors in young people, what contributed to a more aggressive behavior and poor prognosis, Lype et al. (2001) demonstrated that most tumors are well differentiated with a 66.3% rate of cases in stages III and IV of the disease 8. Differently from the observations of some authors, Lype et al. (2001) demonstrated a similar survival rate in young patients when compared to older patients.8

DISCUSSION

It is difficult to determine the age range in which the term "young patient" would apply, considering that many different studies have determined different age ranges. It leads to lack of epidemiological characterization, and this fact may be responsible for not allowing the definition of the increase in cancer rates. Publications have reduced number of cases, which prevents statistical analysis of results 13.

The average incidence of oral SCC, putting together all studies addressed in this paper, was 5.8%, ranging from 0.24% to 15.75%. However, scientific literature shows, as a whole, an increased rate of young patients affected by head and neck SCC, more common in the tongue and in females, and mainly after the 70's. The increase ranged on average from three percentage points up to 62% of tongue carcinoma 10. Despite the increase in oral carcinoma in young patients after 1970, oral carcinoma rates in general have reduced 10. This fact raises our concerns about risk factors to the disease, which seem to be different, given that the pathology has decreased in patients over 40 years.

Some factors could have increased this incidence, such as more advanced methods of diagnosis, increase in number of stomatologists and oral pathologists, more reference centers for diagnosis, computer-based centers, growing concern about compilation of data and medical chart documentation, globalization that leads to greater access to world data with publications and scientific information, increase in number of information campaigns that motivates patients to look for treatment, among others. Moreover, in general, younger patients, especially women, are more concerned about esthetics and wellbeing, which can be understood as a reason that motivates them to look for treatment earlier. There is still another factor that can be considered in view of the sudden increase in number of tongue carcinomas in young people: the tongue is the easiest site for visualization, that is, other intra-oral lesions may take longer to be perceived, given that at first they are not painful, leading to increased age range at the time of diagnosis.

The number of young patients with oral carcinoma reported in the literature is small, raising the need for multicenter and extensive studies to confirm the increase in incidence already reported by the literature. Standardization of age range is essential to convey further reliability to epidemiological studies.

Higher incidence of SCC in young people in public hospitals, reported by Hart et al. (1999), points to the need for investigation of social-economic aspects involved in the disease 17. There was no study found in the literature that could clarify social-economic conditions of the studied group, data that could be extremely useful in determining risk factors.

Higher prevalence of oral carcinoma in African-descendents was observed, which is not in agreement with the literature concerning older age ranges; however, we should take into account the relevance of such information because it is extremely difficult to define racial groups, especially in countries with massive miscegenation, such as in Brazil.15,19

As to preferred gender, conclusions are doubtful, especially because of the size of samples, since very small samples allow important differences to be left unnoticed. However, large samples may transform irrelevant differences into statistically significant differences. Genders should be assessed separately, so that we can analyze qualitative differences such as mutations, genetic alterations, viral participation and others, rather than quantitative differences.

Many authors admitted there is reduced association of risk factors, such as tobacco and alcohol, in young patients2,7,8,16,20,22, whereas others state its presence, similarly to older patients 17,19,21. What should be taken into account is that regardless of absence or presence of such factors, it is extremely important to define the family history of the patient, because even if present, carcinogenic factors interact for shorter time in young people, which leads us to suspect of genetic predisposition or increase in susceptibility of carcinogenic factors. Moreover, the increase in number of cases of oral carcinoma in young people is contrary to the reduction of alcohol and tobacco consumption, which according to Schantz and Yu (2002) has reduced since the 1970. Conversely, the use of tobacco without smoke has increase in the past 30 years, such as the habit of chewing tobacco, which can be partially responsible for such rates.10 As a possible alternative, it may be that these tumors are genetically distinct in young people, requiring few mutations and, for this reason, clinical behavior is also different. 20

It is necessary to have better understanding of other possible etiological factors rather than tobacco and alcohol use. Absence of traditional risk factors in a significant proportion of young patients affected by the disease and the shorter time of exposure to other factors justify the importance of examining other possible causes such as environmental carcinogenic elements, stress, previous viral infections, and history of cancer in the family 13.

New studies are required, such as genetic and social-economic studies, to identify oncogenic viruses such as HPV and Epstein-Barr already identified in different malignant lesions, as well as the action of oncogenes such as p53, telomerase, bcl-2, p21, among others.

There is controversy concerning prognosis, survival and behavior of tumors in young patients. Some say that the progression of the disease is more obscure, whereas others report the opposite. Only few studies presented control cases to determine survival and tumor behavior, which did not demonstrate differences between the younger and the older groups. Moreover, the type of surgical approach is different in both groups, since some surgeons use more radical surgical approaches in young patients, whereas others simply avoid mutilation, since these patients have longer life expectancy. Thus, other studies using control cases and advocated treatment options are extremely important to better understand prognosis.

CLOSING REMARKS

Despite the fact that oral SCC is uncommon in young patients, it should be considered as differential diagnosis with persistent ulcers, erythroplasia, leukoplasia and erythroleukoplasia, especially in higher risk regions, such as the floor of the mouth and the tongue. The earlier the diagnosis and treatment, the higher the likelihood of survival. Prevention of smoking and alcohol intake is mandatory, and any lesion of the head and neck suspected of malignancy, even in young patients, should be carefully analyzed and included in differential diagnosis of SCC.


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