Dr VT Beena Government Dental College Oral and Maxillofacial Pathology Medical College Trivandrum Kerala 695011 India Email: firstname.lastname@example.org
Background: The aim of this study is to highlight the growing incidence of oral cancer in young females without apparent traditional risk factors.
Methods: We present a case series of young female patients with histopathologically diagnosed squamous cell carcinoma of the tongue and no known exposure to major risk factors, reporting to our institution over one year. A review of the literature was carried out to find documented studies on oral cancer in young females.
Results: We found an increase in the number of young female patients presenting with squamous cell carcinomas on the lateral border of the tongue who did not have any of the traditional risk factors associated with the disease, which is in contrast with the number of male patients presenting with the same disease.
Conclusions: Our study highlights the increasing incidence of oral cancer in young females without apparent traditional risk factors, an area of growing concern. Published studies in this particular group are limited. Nevertheless, the situation is alarming owing to the seriousness this problem poses for the community. More research is required to determine the aetiological and risk factors associated with this outcome.
Oral cancer is a serious and growing problem worldwide. Oral and pharyngeal cancer, grouped together, is the sixth most common cancer in the world.1 Oral cancer represents approximately 3% of all cancers in the western world; 95% of these cancers are squamous cell carcinoma (SCC). The incidence increases with age and is more common in men. The tongue is the most commonly cited location and accounts for approximately 25% to 40% of oral cancers.2
Oral cancer typically occurs in an older age group, particularly in males, with a long history of tobacco use and alcohol consumption. However, recently there has been a reported increase in the incidence of oral cancer in the younger population, below 40 years of age, who have not been exposed to the traditional risk factors for an extended period of time.3–5 What is most alarming is the distinct subsample of younger patients, particularly females, who reported little or no exposure to any of the major risk factors and with the tongue being the most commonly involved site. This increase in incidence has raised concerns worldwide.6–8 In this article, we present a series of four cases of young non-habitué females who have been histopathologically diagnosed with SCC of the lateral border of the tongue reporting to our institution over one year.
A 27-year-old female visited our institution, the Government Dental College, Trivandrum, India, complaining of an ulcer on the right side of the tongue for the past two years. On examination, an ulcerative lesion 3 × 2 cm was found on the right posterolateral border of the tongue (Fig 1). The margins of the ulcer were irregular, indurated and covered with slough. There was no relevant medical history or history of tobacco and alcohol use. TNM staging of the lesion was evaluated and found to be Stage II (T2 N0 M0). Histopathologically, the lesion was diagnosed as poorly differentiated SCC (Fig 2). Despite hemiglossectomy and radical neck dissection, the patient died five months after presentation.
A 32-year-old female presented to the outpatient department of the Goverment Dental College, complaining of a non-healing ulcer on the left side of the tongue for the past two years with pain at the same site for the past two weeks. On examination, a lesion 2.5 × 1.5 cm was found on the left posterolateral border of the tongue (Fig 3). The margins of the ulcer were irregular and indurated. The patient’s medical history was insignificant and she denied any tobacco or alcohol use. The TNM staging was Stage II (T2 N0 M0). On biopsy, the lesion was diagnosed as moderately differentiated SCC (Fig 4). The patient underwent total excision of the lesion with radiotherapy. Follow-up has been uneventful.
A 35-year-old female came to the outpatient department of the Government Dental College complaining of a non-healing ulcer on the left side of the tongue for the past two months. On examination, there was an ulceroproliferative lesion 2 × 2 cm on the left border of the tongue with erythematous areas anterior and posterior to it (Fig 5). The margins of the ulcer were indurated. There was no history of tobacco or alcohol use and the patient’s medical history was insignificant. It was found to be a Stage II (T2 N0 M0) lesion. The lesion was diagnosed as moderately differentiated SCC histopathologically (Fig 6). The patient was treated with surgery and later radiotherapy. No recurrence has been noted in the follow-up to date.
A 40-year-old female visited our institution complaining of an ulcer for the past four months. On examination, a lesion 2.5 × 1.5 cm was found on the left posterolateral border of the tongue (Fig 7). The margins were irregular and indurated. There was no relevant medical history nor did the patient have a history of tobacco or alcohol use. The TNM staging of the lesion was found to be Stage II (T2 N0M0). Histopathologically, the lesion proved to be a moderately differentiated SCC (Fig 8). Following surgery and radiotherapy, there appears to be no recurrence to date.
Oral cancer typically occurs in elderly males over the age of 50, mostly with a history of high tobacco use and alcohol consumption, and is rarely found in the young. However, numerous epidemiological studies have reported an increasing trend in tongue cancer among young patients.9–12 In most of the studies, 4% to 6% of oral cancers currently occur in patients younger than 40 years of age. An analysis of combined tumour registry data from Denmark, Sweden, Norway and Finland showed that between 1960 and 1994, 5.5% of tongue cancers occurred in patients aged 20–39 years. The posterolateral border of the tongue was the most implicated site for oral SCC in this study.13
Jones and colleagues in 1989 reported that in patients younger than 40 years of age, females with tongue cancer outnumbered males by almost 2:1.14 Similar findings were earlier reported by Byers,15 Callery,16 McGregor et al.,7 and Venables and Craft.17 However, the study by Clark et al.18 did not show any gender differences. Rosenquist’s study,19 which also evaluated risk factors, showed a tendency for females to have a greater risk than males for developing oral and oropharyngeal carcinoma at any given level of tobacco consumption.
A comparative literature review of possible risk factors for oral cancer in young adults conducted in 2001 revealed that only a few studies had a high proportion of heavy smoking and alcohol consumption associated with oral cancer, whereas most studies found no association.3,15,20 Two other case control studies reported that traditional risk factors were present in young patients but they questioned whether the length of exposure was significant enough to be considered aetiologic.4,5 Studies on patients under 40 years of age also point to a high proportion of females patients with no apparent aetiological factors.6,21 It was also suggested that factors other than tobacco and alcohol might possibly be involved in oral cancer in the Indian population.22
Molecular behaviour patterns of young and old head and neck carcinoma patients reveal no significant differences in expression of cell cycle proteins (p53, p21, Rb, MDM2) between the two age groups.23 In an attempt to understand the molecular behaviour of tongue carcinoma in a young population without risk factors, p53 expression was studied. It was found that p53 was mutated in 51.5% of tumours in young patients, and an intense p53 expression was associated with large sized tumours. These findings were similar to reports of the normal age variant.24 Lingen and colleagues25 found that although 81% of their group of patients overexpressed p53, none demonstrated mutations in the specific exons 5 to 9 of the p53 gene as was seen in patients with risk factors. This suggests that the molecular mechanisms, by which the young individuals with no risk factors had altered p53 function in oral SCC, may differ from those of the more typical population of affected patients with risk factors.
The reported increased incidence of tongue cancer in young females with no history of tobacco or alcohol use has raised interest in aetiologic factors other than the traditional. Some researchers have suggested genetic susceptibility, viral infection, hormonal and immunologic modulations, and other systemic diseases. Genetic predisposition is also considered a contributing factor to oral cancer. It has been found that patients with Fanconi’s anaemia have an increased risk of developing SCCs, especially of the tongue.26 Miller and Johnstone identified HPV in 46.5% of SCCs, 29.5% of verrucous carcinomas, 26.2% of intraepithelial neoplasias, 22.2% of benign leukoplakias and 10% of normal oral mucosa.27 One study found no difference in the incidence of human papillomavirus (HPV, subtypes 16 and 18) between young (<50 years) and older (>50 years) oral cancer patients.28 In contrast, Ringström and colleagues showed that patients with HPV 16-positive head and neck tumours were younger than patients with HPV negative tumours.29 Poor nutrition has been associated with cancer development and increased fruit and vegetable consumption has been shown to provide a certain amount of protection from the development of cancer.30 Even immunosuppression has been linked to tongue cancer in younger patients, which suggests that a compromised immune system puts patients at risk.31 Association of oral cancer to other systemic diseases like diabetes mellitus and nutritional deficiencies in females has also been mentioned. Dikshit et al.32 in a cross-sectional study reported the association between diabetes mellitus and premalignant oral lesions among females but not males. Diabetic women are at an increased risk of developing leukoplakia and erythroplakia. It has been suggested that women might have poorer metabolic control, leading to greater use of insulin and possibly more oxidative damage to DNA.32
Breast cancer, one of the most common cancers in females, may share certain aetiologic factors such as genetic susceptibility and variation in hormone levels which are also implicated in the development of oral cancer. Extensive studies have shown that increased serum levels of oestrogen and testosterone increase the risk of developing breast cancer. Postmenopausal women on hormone replacement therapy have an estimated 2.3% increased risk for each year of use.33 Mutations in the BRCA1 and BRCA2 genes carry high lifetime risks of breast and ovarian cancer, and more moderate risks of other cancer types.34 Such similarities in the aetiological factors between breast and oral cancer could prove to be a pointer to future research directions as yet unexplored.
There are controversial reports on the prognosis for young cancer patients as compared to older cancer patients. Sarkaria and Harari in their review of the literature suggested that the outcome for young tongue cancer patients was worse than that for the older historical controls.35 On the contrary, no significant differences in survival have been found between the two age groups.36–38 Increased survival rates for young patients with tongue cancer have also been reported.7
An intriguing finding was that all the cases presented in our series were of moderate or high grade differentiation, but again histological grading as a prognostic predictor is a matter of controversy.
Oral cancer in the young is quite rare but its increasing incidence in females, especially when not associated with the traditional risk factors of tobacco and alcohol use, is a growing concern. Epidemiologic reports highlight this changing trend. In this article, we have presented a case series of four young female patients who reported to our institution over one year with carcinoma of the tongue and no apparent associated traditional risk factors. Though the number of cases reported in this series may be considered statistically insignificant, the aim of this article is to alert the clinician that even young non-habitué people have the potential to develop oral cancer and that no lesion should be easily dismissed.
Currently, most of the focus of research is on the therapeutic and prognostic aspects of oral cancer. Even published studies aimed at evidence of risk factors and aetiology of oral cancer in young non-habitué females are few. Efforts to improve the understanding of the aetiology and pathogenesis of oral cancer in conjunction with the sexual dimorphism of cancer in females compared to males would be worth pursuing. Further studies in molecular biology and genetic susceptibility are also necessary to identify the mechanism by which many young patients, especially females without any traditional risk factors, go on to develop invasive carcinoma of the tongue.