Grand Challenges in Oral Cancers

Abstract

Oral squamous cell carcinomas (OSCC), arising from surface epithelium, constitute more than 90% of all oral cancers and, in many studies, the term oral cancer is applied as synonymous of OSCC. OSCC, together with SCC from pharynx, larynx, nasal cavity, and paranasal sinuses, belongs to the group of head and neck SCC, but due to increasing knowledge of specific risk factors, different genetic mutations and epigenetic changes and, more importantly, distinct biological and clinical behaviors, tumors from those different sites must be studied separately. Other neoplasms may also arise in the oral cavity, including those derived from connective tissues, minor salivary glands, lymphoid tissues, melanocytes, and odontogenic apparatus, as well as metastasis from distant tumors. Due to their relatively low incidences, important areas of future research must include etiopathogenetic mechanisms, features allowing differential diagnosis, therapeutic strategies (particularly target-specific interventions), and prognostic markers. OSCC is one of the most prevalent cancers worldwide, with a global incidence of more than 350,000 new cases and 177,000 deaths every year, though with considerable geographic and environmental risk factor differences [1]. The incidence of OSCC has been decreasing in some areas of the world, but the incidence has risen in some countries (mainly low-income countries) and among females [2, 3]. An alarming increase in the incidence of OSCC in the younger age group (≤45 years-old) has also been observed. While the use of all forms of tobacco and alcohol explains this increasing incidence in some countries and among females, as ~80% of the world's smokers live in developing countries and females are more exposed to tobacco and alcohol nowadays than before, they do not explain the incidence among younger cancer patients, who, in most of the cases, lack those traditional risk factors or, when present, the time of exposure is much shorter. In this sense, some specific issues regarding OSCC in the younger age group need to be addressed, including risk factors, patterns of inheritance of predisposing genetic alterations, clinical behavior, and prognosis. Furthermore, more effective programs, particularly in developing countries, to eliminate or reduce tobacco (smoking and chewing) and alcohol consumption would be of great value for reducing the incidence of OSCC and other cancers related to those traditional risk factors. Oral potentially malignant disorders (OPMD), mainly represented by leukoplakia, erythroplakia, oral submucous fibrosis, and proliferative verrucous leukoplakia (PVL), are well-recognized to precede the development of OSCC. In this group, PVL seems unique, since it does not consistently show association with classical environmental agents, its natural history seems different than any other OPMD, and the potential of malignant transformation is the highest among OPMD [4]. The potential of other OPMD, such as oral lichen planus (OLP), remains still somewhat questionable. However, several meta-analyses published in the last 3 years showed a low, but consistent, transformation of classical OLP to oral cancer, confirming that OLP should be considered as an OPMD [5–7]. The early diagnosis and treatment of OPMD is essential to minimize or even eliminate the risk of malignant transformation. However, not all disorders are amenable to curative treatment, and the transformation does not occur in every single case. Although presence and intensity of dysplasia, representing the collection of changes in cellular morphology and tissue architecture at the histopathological standpoint, are considered the main parameters related to malignant transformation of OPMD, the histological assessment of the epithelial dysplasia is a source of substantial subjectivity, and in a meta-analysis, the mean overall transformation rate of OPMD with dysplasia was only 12.1% [8]. Therefore, the characterization of biomarkers to define the magnitude of risk, the mechanisms and the period of progression for transformation is of great importance, in order to rationally schedule treatment or follow-up and to plan cost-effective oral screening programs. OSCC is considered a very aggressive tumor and the majority of patients displays a locoregionally advanced disease at diagnosis, for which multimodality therapy is required. Tumor invasion, lymph node metastasis and high rates of locoregional recurrence, besides development of second primary tumors, are the leading causes of death in OSCC patient. However, even at early stage, particularly tumors of the tongue and floor of mouth may be very aggressive, with increased tendency to invasion and metastasis. In this context, survival rates are of ~40–50% and these rates have not significantly changed over the past decades [9]. Although our understanding about the biological processes involved in cancer development and progression is evolving and many biomarkers have been suggested to significantly impact diagnosis and prognosis of OSCC, no biomarker has yet met the stringent criteria that are needed to be used in clinical practice. Thereafter, it is of consensus among all professionals involved in the field that markers with potential clinical applications, such as early diagnosis, therapeutic targets, responsiveness to treatment, prognosis and post-therapeutic monitoring, are urgently needed to improve clinical management of OSCC. Investigations aimed to characterize OSCC biomarkers should ideally take into consideration some aspects, including prospective analyses of several markers, as a panel, in large cohorts, preferably multicenter, and application of quantitative and complementary assays to capture the impact of biomarkers in different scenarios (the vast majority of studies is based exclusively on immunohistochemistry without a standard pattern of quantification). Furthermore, authors should be aware that cancer heterogeneity is an...