Oncology Discovery ISSN 2052-6199 | Volume 3 | Article 1 Review Open Access Preneoplasia and carcinogenesis of the oral cavity Naoki Watanabe1, Tsunemasa Ohkubo2, Masahito Shimizu3 and Takuji Tanaka1* *Correspondence: [email protected] CrossMark ← Click for updates 1Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu City, Gifu 500-8513, Japan. 2Department of Oral Surgery, Takayama Red Cross Hospital, 3-11 Tenma-cho, Takayama City. Gifu 506-0025, Japan. 3Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. Abstract Oral cancer, ranking sixth in the cancer incidence worldwide, is one of the most common neoplasms. Preneoplastic or premalignant (precancerous) lesions are lesions that can potentially transform into malignancy in a variety of tissues, including the oral cavity. Such oral lesions may be caused by tobacco use, exposure to the human papillomavirus and chewing of the betel nut. These substances contain carcinogens and/or tumor promoters. The mucosa of the oral cavity is covered with squamous epithelium and is relatively resistant to injury. However, exposure to these substances can cause the mucosa to undergo changes. The changes are usually initiated by a leukoplakic patch. While some leukoplakic patches recover and resolve, others progress to squamous cell carcinoma with or without invasion. Other premalignant lesions include oral submucous fibrosis, which is a potentially malignant condition caused by the abuse of the betel nut. Understanding the histology, premalignant states and molecular mechanisms of oral carcinogenesis may facilitate the development of novel strategies for the prevention and treatment of oral cancer. In addition, early detection is of critical importance to improve the survival rates of patients with oral cancer. In this review, we will summarize these aspects of oral cancer development, beginning from the histology of the oral cavity. Keywords: Oral cancer, premalignant lesions, oral carcinogenesis, dysplasia; animal model, molecular mechanisms, chemoprevention Introduction cancer is generally more prevalent in males, but in the high-risk Over 90% of all malignancies (Table 1) of the oral cavity are areas of southern Asia, the rates in females are equivalent to squamous cell carcinomas (SCCs) arising from the lining mucosa, those in males [5]. The incidence of oral tumors has recently the squamous epithelium. Worldwide, oral cancer (buccal cancer) been increasing in developed countries, with the increase in is the sixth most common cancer, representing about 5.5% risk being seen in younger people, particularly young females of all malignancies. It is more common than uterine cervical [6]. It is mainly seen in males over middle age (although it cancer [1]. The incidence varies by geographical regions, being is increasing in younger people), tobacco users, and lower higher in the developing countries, with relative frequencies of socioeconomic groups. almost 50% in some parts of southeast Asia and Brazil [2]. It is The etiological factors [7] acting on a genetically susceptible relatively uncommon in the developed world, except in parts individual include tobacco use (75% of people with oral cancer of France. Age-adjusted incidence rates of oral cancer range smoke), betel use (Bidi leaf, which is often combined with from 2.2 per 100,000 males in Japan and several industrialized tobacco, spices, slaked lime, and areca nut), alcohol consumption, countries to 15-30 per 100,000 in southern Asia [3], with more a diet poor in fresh fruit and vegetables, infective agents than 500,000 new cases projected worldwide annually [4]. (Candida, viruses), immune deficiency, and (in the case of lip In Japan, the number of annual deaths from all oral cancers carcinoma) exposure to sunlight (Table 2). The oral cavity can showed a 4.5-fold increase from 698 to 3,155 from 1950 to 1993. be the site of a variety of HPV-related lesions [8-10], some of Tongue cancer is the most common type of oral cancer, and which are microscopically and behaviorally analogous to those contributes to about 40-60% of all oral cancer deaths. Such oral located in the genital tract [11]. The verruca, condylomas, and © 2015 Tanaka et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Watanabe et al. Oncology Discovery 2015, http://www.hoajonline.com/journals/pdf/2052-6199-3-1.pdf doi: 10.7243/2052-6199-3-1 Table1. The histopathology of oral malignant neoplasms. These second primary neoplasms are found in up to 25% of people who have had oral cancer for over three years, and in Common Squamous cell carcinoma (SCC) up to 40% of those who continue to smoke. Similarly, patients Specific types of SCC: with lung cancer are at risk of developing second primary Verrucous carcinoma oral cancers. Such findings indicate the presence of so-called Basaloid SCC “field cancerization” [22,23]. Adenoid SCC Review Adenosquamous carcinoma Anatomy Papillary SCC The oral cavity is externally bounded by the internal mucosa Uncommon Malignant salivary gland tumor; malignant of the cheeks and the vermillion border of the lips. It is melanoma; malignant lymphoma; malignant superiorly formed by the hard and soft palates, and inferiorly neoplasms of bone and connective tissue, some by the anterior two-thirds of the tongue, with the attached malignant odontogenic tumors; maxillary antral carcinoma; Langerhans’s cell histiocytoses; mucous membsranes of the floor of the mouth. The posterior Kaposi’s sarcoma; metastatic neoplasms (from boundary of the oral cavity, which forms a junction with the breast, lung, kidney, stomach or liver cancer) oropharynx, is the fauces. This is defined superiorly by the posterior edge of the soft palate and uvula and laterally by Table 2. Etiologic factors of oral cancer. the tonsillar pillars. The inferior margin corresponds to a line across the circumvallate papillae of the tongue. Tobacco smoking: pipes, cigars, cigarettes, bidis, reverse smoking Smokeless tobacco: snuff dipping, tobacco sachets, tobacco chewing Histology Most of the oral cavity is lined by nonkeratinizing squamous Chewing habit: betel chewing, betel quid (pan), areca nut epithelium. Portions directly involved in chewing, including Alcohol: spirits, wines and beers, alcohol and tobacco synergism the hard palate and parts of the gingiva, are lined by squamous Diet and nutrition: iron deficiency, vitamin A, E and C deficiencies, mucosal epithelium with varying degrees of orthokeratotic nutritional deficiencies and alcoholism and parakeratotic epithelium. These are associated with Dental factors: poor oral hygiene, faulty restorations, sharp edges considerable thickening of the underlying rete ridges. Identical of teeth, ill-fitting dentures histological changes develop in areas of chronic irritation, Ultraviolet light which are most often associated with poorly fitting dentures. The tongue is covered by specialized filiform, fungiform and Viruses: herpes simplex virus (HSV), human papillomavirus (HPV), human immunodeficiency virus (HIV) circumvallate papillae involved in chewing and taste. Scattered melanocytes are normally present in the oral squamous Immunosuppression: drug-induced, etc. epithelium. They are difficult to find on hematoxylin and Chronic infection: candidiais, syphilis eosin (H & E)-stained sections, but appear as clear cells in the Occupational: textile workers, etc. basal epithelial layer and are positive for the S-100 protein immunohistochemically. The stratified epithelium lining papillomas often exhibit koilocytosis as a sign of cytopathologic the papillary wall of the cleft contains numerous taste buds, effect. Atypical nuclear changes may be present, especially in which show neurone-specific enolase-positive reactions HIV-positive patients [12]. An etiologic role for HPV has also immunohistochemically. The lamina propria of the oral cavity been suggested for verrucous carcinoma [13] and squamous is filled with seromucinous glands, which are prominent in the cell carcinoma, including some of its variants [14,15]. The lamina propria of the hard palate. The stroma around teeth benign oral lesions are statistically associated with HPV often contains epithelial nests of apparent odontogenic origin. types 2, 4, 6, 11, 13, and 32, and the malignant ones with HPV types 16, 18, and 33 [11,16]. Among the carcinomas, those Oral premalignancy with the highest incidence of HPV detection are the poorly Potentially premalignant lesions or conditions may include differentiated non-keratinizing tumors of the tonsil seen in some fibrosis and chronic immunosuppression. About half of young individuals [17,18]. Many of the latter tumors express oral carcinomas have associated leukoplakia. Rare causes of oral p16 protein [19]. HPV-positive oropharyngeal cancers are cancer include tertiary syphilis, discoid lupus erythematosus, also more likely to show basaloid morphology [20]. Human dyskeratosis congenital and Plummer-Vinson syndrome papillomavirus (HPV) vaccine is now approved for use to (iron deficiency and dysphagia). The two most common and prevent cancers developing in several tissues, including oral well-documented clinical oral tissue