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Contact us at firstname.lastname@example.org Chapter 5 Oral Squamous Cell Carcinoma in Young Population — Risk Factors, Clinical Presentation, and Prognosis Ligia Buloto Schmitd, Kellen Cristine Tjioe, Agnes Assao and Denise Tostes Oliveira Additional information is available at the end of the chapter http://dx.doi.org/10.5772/60712
1. Introduction The oral squamous cell carcinoma is a particular type of cancer classically described as a tobacco- and alcohol-related disease affecting mostly elderly male patients. However, epide‐ miologic studies have demonstrated an increasing incidence of young individuals with oral cancer. Interestingly, the clinicopathological profile, etiology, risk factors, and outcome of patients with early-onset disease seem to present several differences compared to late-onset oral carcinoma and these discrepancies are discussed below.
2. Clinical manifestations Retrospective studies including elderly and young patients have shown that the incidence of squamous cell carcinoma (SCC) of the mouth in young people is low but presents an increasing tendency . In fact, there is certain heterogeneity of the cutoff age employed in the studies.
Most authors consider young patients as those who are under 40 or 45 years [2-6] whereas few investigations select individuals under 20 or 30 years [7-9]. The incidence of oral cancer in patients younger than 40 years of age varies between 0.4–3.6%, but it can reach 6.7% in studies considering 45 years as the cutoff point . Due to its rarity, most investigations deal with a small sample of patients, and conflicting results have been published regarding the epide‐ miological aspects of oral SCC.
The clear male predominance found in late-onset lesions is not found in the early-onset counterparts. Men are still more affected than women but only slightly more, with a F:M ratio © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
132 Contemporary Issues in Head and Neck Cancer Management varying from 1:1.2 to 1:4.9 [11, 12]. These data show an evident augmentation in the number of young women affected by oral SCC. The differences between sex distribution previously observed may be due to smoking and drinking habits, which are more socially acceptable for both genders currently .
The most common oral subsite for SCC in young patients is the tongue, with 39–77% of the cases [13, 14]. A study conducted in Taiwan found a higher incidence of oral SCC in the buccal area (53.6%) in comparison with the tongue (42, 8%), but betel chewing was common among these patients . Other retrospective reports in Germany and Brazil showed a slightly higher incidence of oral SCC in the floor of the mouth, followed by the mobile tongue [12, 16].
The typical clinical appearance of oral SCC in young patients is an ulcer, often intermixed with white plaque and/or reddish areas. Kuriakose et al.  noted that lesions in young patients were predominantly invasive as compared with the exophytic lesions found in older patients [10, 17]. On the other hand, Falaki et al.  reported exophytic lesion with ulcer as the most common clinical presentation in younger individuals.
Figures 1 and 2 illustrate a 35-year-old young man who presented with a white plaque intermixed with erythroplastic areas in the right border of the tongue. The duration of the lesion was of one year, and the patient reported slight pain. Moreover, the individual did neither consume tobacco nor alcohol. Incisional biopsy confirmed the diagnosis of SCC that was staged lately as T2N0M0. The patient was submitted to partial glossectomy with supra‐ omohyoid selective neck dissection of the same side and radiotherapy. The one-year followup was uneventful.
Figure 2: Arrows indicate a slightly elevated and indurated border of the lesion showed in Figure 1, demonstrating the infiltrative characteristic of the tumor.
Figure 2. Arrows indicate the lesion showed in Figure 1.
Elevated and indurated borders were confirmed by palpation, demonstrating the infiltrative growth of the tumor. uncommon . Other signs and symptoms can be dysphagia, weight loss Regarding the symptoms, initial local pain is and otalgia (26.5%, 26.6% and 37.5%, respectively) , but they seem to be related to the size and anatomic location of the tumor.
Regarding the symptoms, initial local pain is uncommon . Other signs and symptoms can be dysphagia, weight loss and otalgia (26.5%, 26.6% and 37.5%, respectively) , but they seem to be related to the size and anatomic location of the tumor. The duration of the symptoms before diagnosis can vary, but reported data show that most of the patients had early stage disease at the moment of diagnosis, that is, from 52-95% of the patients presented with lesions graded as T1 or T2, usually without neck metastasis [13, 21]. Fang et al.  reported that 80% of patients younger than 40 years-old with oral SCC presented lesions staged as T1 or T2 and only one tumor with positive node metastasis, appearing to be weakly aggressive at diagnosis.
However, the clinical result was poor, as 10 (66.7%) patients exhibited recurrence and five (33%) patients succumbed to the disease .
The delay before diagnosis is usually between few weeks and 10 months [23, 24].
3. Microscopic findings
The microscopic features that define an oral SCC do not differ between young and old patients.
SCC is an invasive epithelial neoplasm with varying degrees of squamous differentiation.
Disorganized stratified squamous epithelium forming strands and islands of bizarre epithelial cells presenting severe dysplasia infiltrating subjacent submucosa is observed. Dyskeratosis, polymorphism, hyperchromatism, atypical mitosis and loss of nucleolus-nucleus and nucleuscytoplasm ratio are also marked cellular characteristics , as shown in Figures 3 and 4.
The tumors are traditionally graded into well, moderately, and poorly differentiated SCC.
According to the World Health Organization (WHO), well-differentiated carcinoma resembles closely normal squamous epithelium. Moderately differentiated carcinoma contains distinct nuclear pleomorphism and mitotic activity, including abnormal mitosis, and there is normally 134 Contemporary Issues in Head and Neck Cancer Management less keratinization. In poorly differentiated carcinoma, immature cells predominate, with numerous typical and atypical mitosis, and minimal keratinization. Most of the SCCs are moderately differentiated . The studies in young population also showed a higher incidence of moderately differentiated oral tumors, ranging from 40.9% to 70% of the sample [7, 20, 26-29]. Hilly et al.  and Garavello et al.  found worse prognosis and higher indexes of moderately and poor differentiated tumors in their sample. Controversially, Hyam et al.  found similar prognosis associated with 67% of poorly differentiated tumors. Grading by differentiation is of limited prognostic value, as compared to the pattern of invasion .
Figure 3. Neoplastic squamous epithelium infiltrating subjacent submucosa (H&E original magnification X50).
4. Etiology/risk factors
4.1. Tobacco and alcohol In recent years, an increasing number of young patients, who declare to never having smoked or consumed alcohol excessively, are diagnosed with oral SCC [17, 31]. Tobacco smoke and alcohol abuse are considered well-established risk factors for oral SCC in older population. Otherwise, in young patients, these classical risk factors cannot be considered as the major ones for oral cancer [10, 17, 32, 33], if the period of abuse is not enough to create carcinogenesis .
On the other side, some studies report that tobacco use starts during adolescence , usually before 16 years old, making probable that before the age of 40 years, patients have an accumulated risk of more than 21 years of consumption, being more susceptible for the oral cancer .
Probably, the pathogenesis of oral SCC in young people involves multiple factors, as genetic and others new behavioral factors [32, 33]. It seems that tobacco and alcohol consumption are not the main etiological factors for oral SCC in young patients.
4.2. Genetic factors Genetic predisposition for cancer development at young age, especially in those patients with no recognized risk factors seems to be preponderant . Chromosome fragility, DNA ploidy abnormalities and increased familial risk of head and neck SCC have already been reported in young patients [26, 34, 35].
Considering the familial risk, a clear significant relative risk of SCC exists in first-degree family members of those who suffered head and neck cancer , especially when there is no recognized risk factor associated. Oral cancer has been associated with higher chromosome fragility and instability in youngsters, compared to elderly .
Genetic instability is an important molecular mechanism for head and neck cancers . Gain and loss of specific chromosome regions in DNA are responsible for head and neck cancers, for example the 3p or 9p21 region, which are early events strictly related with head and neck cancer development, but that are not commonly seen in young people . It is supposed that a completely different model of tumorigenesis exists, at a molecular level, in young people.
One essential step for tumorigenesis is deregulation of normal cell cycle regulatory system, especially in genes that control G1 to 2 phase progression in cell cycle . The amplification of the gene CCDN1 was noted to be more expressive in young people . CCDN1 is a protooncogene that encodes cyclin D1, a key regulator of G1 phase in cell cycle. The overexpression of cyclin D1 was found to be more prominent in young people , and it was correlated with disease-free survival in younger and elderly patients. Instead of these findings, larger studies are required to confirm the prognostic value of CCDN1 in young patients.
136 Contemporary Issues in Head and Neck Cancer Management
4.3. Behavioral and other factors 4.3.1. Marijuana consumption Several cases reported in the literature [38, 39] suggest an association between marijuana smoking and head and neck cancers and respiratory cancers, but this correlation is not conclusive.
The use of marijuana has been speculated as a risk factor for oral cancer in young people .
The main reason is that marijuana smoke contains carcinogens similar to those in tobacco, and marijuana smoking involves greater inhalation and longer retention of marijuana smoke .
However, the potential of carcinogenicity of tetrahydrocannabiol (THC), the major psychoac‐ tive ingredient in marijuana, is not clear yet , but it is evident that cannabinoids have an effect in tumorigenic or antitumorigenic role . The patient with oral SCC illustrated in the Figures 1 and 2 confirmed frequent marijuana use when he was a teenager.
Some chronic immunodeficiency states (Bloom syndrome, Wiskott-Aldrich syndrome), or even immunosuppression regimes following organ transplantation  and anemia (Patterson Kelly/ Plummer Vinson syndrome, Fanconi anemia) , might play important roles in carcinogenesis in young people. Specifically, Fanconi anemia has an associated higher risk for developing head and neck cancer, estimated to be 40% by the fourth to sixth decade of life.
Mutations in telomerase complex are responsible for Fanconi anemia and regarding its malignant transformation, telomeres are repeatedly shortened precipitating a genetic insta‐ bility, allowing the progression to a malignant neoplasia .
Another distinct group that compound young head and neck cancer patients is those with cancer during childhood. The probability of a second synchronous tumor or metachronous primary tumor is estimated in 3–12% in 20 years of survival. Also, chemotherapeutic drugs and radiation can induce malignancies as side effects [7, 42].
A well-defined concept is that a diet rich in fruits and vegetables, with antioxidant properties, has a protective role against oral cancer . A significant reduction in the risk of oral SCC was found among females consuming three or more portions of fresh fruits and vegetables daily [43, 44]. However, this factor is preponderant for the population in general and there are no studies on specific dietary behavior for young people.
4.3.4. Viral infections
that rarely progress into malignancy whereas the high-risk ones have oncogenic capability, leading to the development of cancer. The HPV-16 and HPV-18 are the major high-risk types that are present in anogenital and head and neck cancers .