Cancers of the Oral Mucosa
- Author: Crispian Scully, MD, PhD, MDS, CBE, MDS, MRCS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FRCPath, FMedSci, FHEA, FUCL, DSc, DChD, DMed(HC), Dr(HC) ; Chief Editor: Dirk M Elston, MD more...
Background
Approximately 90% of oral cancers are squamous cell carcinoma (SCC), which is seen in older men, typically on the lip or lateral part of the tongue. Note the image below.
Oral squamous cell carcinoma in the most common intraoral site manifesting as a chronic, indurated ulcer. Oral SCC (OSCC) is particularly common in the developing world. There is concern about an increase in younger patients. The etiology appears to be multifactorial and strongly related to lifestyle, mostly habits and diet (particularly tobacco alone or in betel, and alcohol use), although other factors, such as infective agents, also are implicated. Immune defects, defects of carcinogen metabolism, or defects in DNA-repair enzymes underlie some cases. Sunlight exposure predisposes to lip cancer.
Findings from the history and clinical examination by a trained diagnostician are the primary indicators of OSCC, but the diagnosis must be confirmed histologically.
Pathophysiology
In oral squamous cell carcinoma (OSCC), modern DNA technology, especially allelic imbalance (loss of heterozygosity) studies, have identified chromosomal changes suggestive of the involvement of tumor suppressor genes (TSGs), particularly in chromosomes 3, 9, 11, and 17. Functional TSGs seem to assist growth control, while their mutation can unbridle these control mechanisms.
The regions most commonly identified thus far have included some on the short arm of chromosome 3, a TSG termed P16 on chromosome 9, and the TSG termed TP53 on chromosome 17, but multiple other genes are being discovered.
As well as damage to TSGs, cancer may also involve damage to other genes involved in growth control, mainly those involved in cell signaling (oncogenes), especially some on chromosome 11 (PRAD1 in particular) and chromosome 17 (Harvey ras [H-ras]). Changes in these and other oncogenes can disrupt cell growth control, ultimately leading to the uncontrolled growth of cancer. H-ras was one of the oncogenes that first caught the attention of molecular biologists interested in cell signaling, cell growth control, and cancer. It and the gene for epidermal growth factor receptor (EGFR) are involved in cell signaling.
The genetic aberrations involve, in order of decreasing frequency, chromosomes 9, 3, 17, 13, and 11 in particular, and probably other chromosomes, and involve inactivated TSGs, especially P16, and TP53 and overexpressed oncogenes, especially PRAD1.
The molecular changes found in OSCC from Western countries (eg, United Kingdom, United States, Australia), particularly TP53 mutations, are infrequent in Eastern countries (eg, India, Southeast Asia), where the involvement of ras oncogenes is more common, suggesting genetic differences that might be involved in explaining the susceptibility of certain groups to OSCC.
The rare Li-Fraumeni syndrome is associated with defects in TP53.
Carcinogen-metabolizing enzymes are implicated in some patients. Alcohol dehydrogenase oxidizes ethanol to acetaldehyde, which is cytotoxic and results in the production of free radicals and DNA hydroxylated bases; alcohol dehydrogenase type 3 genotypes appear predisposed to OSCC. Cytochrome P450 can activate many environmental procarcinogens. Ethanol is also metabolized to some extent by cytochrome P450 IIEI (CYP2E1) to acetaldehyde. Mutations in some TSGs may be related to cytochrome P450 genotypes and predispose to OSCC. Glutathione S transferase (GST) genotypes may have impaired activity; for example, the null genotype of GSTM1 has a decreased capacity to detoxify tobacco carcinogens. Some GSTM1 and GSTP1 polymorphic genotypes and GSTM1 and GSTT1 null genotypes have been shown to predispose to OSCC. N -acetyltransferases NAT1 and NAT2 acetylate procarcinogens. N -acetyl transferase NAT1*10 genotypes may be a genetic determinant of OSCC, at least in some populations.
Tobacco is a potent risk factor for oral cancer. An interaction occurs between redox-active metals in saliva and the low reactive free radicals in cigarette smoke. The result may be that saliva loses its antioxidant capacity and instead becomes a potent pro-oxidant milieu.[1]
DNA repair genes are clearly involved in the pathogenesis of some rare cancers, such as those that occur in association with xeroderma pigmentosum, but, more recently, evidence of defective DNA repair has also been found to underlie some OSCCs.
Immune defects may predispose to OSCC, especially lip cancer. OSCC is also now being reported with increased frequency in association with diabetes and systemic sclerosis.
Intraoral OSCC primarily affects the posterior lateral part of the tongue. Spread is local, especially through muscle and bone, and metastasis initially is to the anterior cervical lymph nodes and later to the liver and skeleton.
Epidemiology
Frequency
International
The oral cavity is 1 of the 10 most frequent sites of cancer internationally, with three quarters of cases affecting people in the developing world, where, overall, oral cancer is the third most common cancer after stomach and cervical cancer. An estimated 378,500 new cases of intraoral cancer are diagnosed annually worldwide.
Unfortunately, the parts of the world where oral cancer is most common are also those where descriptive information (ie, incidence, mortality, prevalence) is least available. In certain countries, such as Sri Lanka, India, Pakistan, and Bangladesh, oral cancer is the most common cancer. In parts of India, oral cancer can represent more than 50% of all cancers.
In developed countries, oral cancer is less common but is the eighth most common form of cancer overall; however, the ranking varies a great deal among countries. For example, in areas of northern France, oral cancer is the most common form of cancer in men. Estimates show that in 1980, more than 32,000 new cases of oral cancer were diagnosed throughout the European community. The prevalence of lip cancer appears to be decreasing, but the prevalence of intraoral cancer appears to be rising in many countries, especially in younger people. This is especially true in Central and Eastern Europe.
Mortality/Morbidity
Mortality rates for oral squamous cell carcinoma (OSCC) have increased, primarily in many eastern European countries.
- In Germany, The Czech Republic, and Hungary, almost a 10-fold increase in mortality from oral cancer in men aged 35-44 years occurred within one generation.
- Systematic analyses of cancer mortality data for 28 European countries showed pronounced upward trends in oral cancer mortality in persons aged 35-64 years from 1955-1989.
- Inspection of age-specific mortality rates reveals substantial increases at younger ages in most European countries, thus indicating the existence of strong cohort effects that will lead to increasing levels of oral cancer among males during future decades.
Race
The prevalence of tongue cancer is consistently found to be higher (by approximately 50%) in blacks compared with whites within the same regions of the United States.[2] The prevalence of oral cancer is also generally higher in ethnic minorities in other developed countries.[3]
Sex
Oral cancer affects males more frequently than females, although the ratio is equalizing.
Age
Oral cancer is predominantly found in middle-aged and older persons.
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| Therapies | Examples | Adverse effects |
| EGFR inhibitors (FDA approved) | Cetuximab | Ulcers |
| EGFR inhibitors | Panitumumab, erlotinib in combination with gemcitabine | Ulcers |
| mTOR inhibitors | Deforolimus, rapamycin (sirolimus) and temsirolimus | Ulcers |
| Tyrosine kinase inhibitors (TKIs) of platelet-derived growth factor (PDGF) | Imatinib | Ulcers, dysgeusia |
| TKIs of PDGF and vascular endothelial growth factor (VEGF) | Sunitinib | Ulcers, dry mouth, dysgeusia |
| Raf multi-kinase inhibitors | Sorafenib | Dysgeusia |
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