10 Malignant disease of the oral cavity
In global terms, oral/oropharyngeal cancer is the sixth most common malignancy. In the Western world it accounts for only 2–4% of all malignant tumours although there is now good evidence to show that the incidence is increasing, particularly in younger people. By contrast, in Asia oral/oropharyngeal malig-nancy is the most common malignant tumour, which in parts of India accounts for no less than 40% of all malignancy. It is estimated that globally nearly 500 000 new cases develop annually and that in the year 2000 there were 1.5 million people alive with oral cancer at any one time.
Oral/oropharyngeal cancer is an almost entirely preventable disease, being caused by use of tobacco (with or without alcohol). In the West this is mostly cigarette smoking combined with alcohol abuse; the risk caused by both in combination is greater than the summation of the risks of each individually. In Asia and the Far East the use of Pan in its various forms and reverse smoking are the major aetiologic agents: epidemiological evidence strongly suggests that it is the presence of tobacco in the betel quid which is the major agent, although there seems also to be some relationship to the source of slaked lime and the areca nut itself. In the West, the incidence in women appears to be increasing and there is a worrying increase in the number of young patients, mostly male and particularly with tongue cancer, after a gradual fall earlier this century. This recent trend seems not to be related to tobacco and alcohol consumption and has been observed throughout Europe and North America. The general dental practitioner has a major role in prevention by advising and helping patients to cease tobacco smoking or chewing and moderating alcohol consumption.
Local control of disease at the primary site and the management of neck disease has improved; yet, despite this, cure rates and survival rates have only improved marginally in 40 years, remaining at approximately 55% survival at 5 years. Both recurrence of local disease and failure to control lymphatic metastases in the neck are early events and are a major cause of death. There is no doubt, however, that during the past 20 years great advances have been made in the management of oral cancer, and persistence of local disease and lymphatic metastasis are now less common. Why then have cure rates not improved? Field changes in the upper aerodigestive tract result in the phenomenon of multiple primary cancers. The longer a patient survives a first tumour, the greater the risk of developing a second or third primary tumour either elsewhere in the oral cavity or in the larynx, bronchus or oesophagus.
Even a patient who does not develop a second primary tumour is at risk of developing distant metastatic disease. Metastasis via the bloodstream is a relatively early event in oral cancer, although until recently rarely recognized during life. Currently 20% of all cancer-related deaths in patients with a tumour in the oral cavity/oropharynx are due to distant metastasis with no evidence of disease in the head or neck. Thus oral cancer is a ‘systemic’ disease from an early stage.
Surgical advances have been mainly in techniques of access surgery and in reconstruction. The widespread adoption of lip splitting and mandibulotomy has facilitated safe three-dimensional resections of tumours in the tongue and floor of the mouth in continuity with the lymphatics in the neck. A better understanding of the patterns of invasion of the mandible by adjacent tumour has allowed the development of rim resections, avoiding the sacrifice of mandibular continuity in many cases, without risking local recurrence. In recent years the development of skull base access surgery using well-established oral and facial osteotomy techniques has rendered previously inoperable tumours operable. This is particularly true for tumours extending into the pterygoid, infratemporal and lateral pharyngeal regions.
Primary reconstruction is now the rule, and this is to the great benefit of patients. Earlier techniques were often unreliable and when bony reconstruction was involved it was often delayed. It was reasonably felt that before embarking on such prolonged and insecure techniques a period of time should be allowed to elapse, to demonstrate that local recurrence was unlikely before reconstruction was attempted. With current techniques based largely on muscle flaps—pectoralis major, trapezius and latissimus dorsi—and free tissue transfer based on microvascular techniques—radial forearm, lateral thigh, scapular, fibula and groin—primary reconstruction is not only reliable but produces acceptable functional and cosmetic results.
Megavoltage X-ray beams or electron beams are able to penetrate tissues and can cause cell death by producing lethal damage to DNA. Irradiated cells die as they attempt to divide and because malignant cells generally divide more rapidly than normal cells there is differential cell death. With careful planning and adjustment of dosage and frequency of treatment the tumour cells can be destroyed whilst sparing sufficient normal tissues to allow healing and repair. A typical regimen for an oral carcinoma would be a total dose of 55 Gray given by daily treatments on Monday to Friday over a 6-week period. The daily dose (fraction) is therefore only small and allows for repair of normal tissues between treatments. In most centres, surgery is the primary modality for most patients. Radiotherapy is used as a supplement when the surgical margins of the tumour are not clear or there is extensive nodal metastasis in the neck.
An alternative way of treating tumours with radiotherapy is to implant radioactive materials into the tumour (brachytherapy). Radioactive iridium wires are the most commonly used implants. There is a rapid fall-off of dose with distance, and the technique continuously delivers very high-dose local irradiation with very little damage to adjacent tissues. Therefore the adverse effects of conventional radiotherapy are largely avoided.
Although many single agents or combinations of drugs can result in a response rate of around 60%, there is no evidence that this results in an increase in survival time or cure rate. Some centres advocate the use of induction chemotherapy before surgery but again there is no evidence, based upon prospective studies, that this improves survival. Palliative chemotherapy using agents such as cisplatinum and 5-fluorouracil are sometimes helpful for painful or fungating tumours.
Oral cancer has a predilection for certain sites within the mouth, mostly the lateral margins and ventral tongue, floor of mouth, retromolar trigone, buccal mucosa and palate. Most—more than 85%—are mucosal squamous cell carcinomas. Malignant tumours arising in the minor salivary glands are next in frequency, with lymphomas, malignant melanomas, sarcomas and metastatic tumours making up the remainder.
The association of oral carcinoma with other oral mucosal lesions has been recognized for many years. Often these lesions are in the form of white plaques (‘leukoplakia’) or bright red velvety plaques (‘erythroplakia’), which may be present for periods of months to years before the onset of malignant change and often will be present together with the carcinoma when the diagnosis of malignancy is made. Because of this association, it has been assumed that such lesions lead directly to invasive carcinoma and hence are themselves premalignant. Some white plaques do have a potential to undergo malignant transformation and an examination of established carcinomas will show many to exist in association with white plaques. However, most oral carcinomas are not preceded by, nor associated with, leukoplakia.
Although historically oral leukoplakia has been recognized as premalignant, the risk of malignant transformation is not as great as was previously thought. Early literature suggested a 30% or higher incidence of malignant transformation of these lesions whereas more recent authors quote an incidence of 3–6%. The following oral lesions are now considered to carry a potential for malignant change:
Using the term leukoplakia either in a histological or clinical context is a matter of defining what is meant by the term. The World Health Organization (WHO) has defined leukoplakia as ‘any white patch or plaque that cannot be characterized clinically or pathologically as any other disease’. This definition has no histological connotation.
Clinically leukoplakia may vary from a small, circumscribed white plaque to an extensive lesion involving wide areas of the oral mucosa. The surface may be smooth or it may be wrinkled and many lesions are traversed by cracks or fissures. The colour of the lesion may be white, yellowish or grey; some are homogeneous whilst others are nodular or speckled on an erythematous base. Many lesions are soft whereas other thicker lesions feel crusty. Induration (hardening) suggests malignant change and is an indication for immediate biopsy. It is important to recognize that it is the speckled or nodular leukoplakias which are the most likely to undergo malignant change.
The incidence of malignant change in oral leukoplakia increases with the age of the lesion. One study showed a 2.4% malignant transformation rate at 10 years, which increased to 4% at 20 years. It also showed that as the age of the patient increased so did the risk of malignant transformation: for patients younger than 50 years it was 1%, whereas for those between 70 and 89 years it was 7.5% during a 5-year observation period. Kramer et al. (1978) have shown that in Southern England leukoplakia of the floor of the mouth and ventral surface of the tongue, so-called ‘sublingual keratosis’, has a particularly high incidence of malignant change. Their study suggested that this occurrence was due to pooling of soluble carcinogens in the ‘sump’ of the floor of the mouth.
Tobacco smoking or chewing are undoubtedly important aetiological factors. In Indians who smoke or chew tobacco (often as a component of the betel quid) the incidence of leukoplakia in those of 60 years of age is 20%, whereas in those who neither smoke nor chew tobacco the incidence is 1%.
The role of alcohol in the development of oral leukoplakia is difficult to assess. Few studies have been reported, but it has been shown that in patients with leukoplakia the incidence of excessive alcohol consumption is greater than in those without leukoplakia.
In any patient presenting for the first time with oral leukoplakia a careful history—particularly looking for aetiological factors—and a detailed clinical examination should precede the histological examination of biopsies of any suspicious areas. Suspicion is aroused by any areas of ulceration, induration or where the underlying tissues are bright red and hyperaemic. Vital staining with toluidine blue can be used to guide the clinician to those sites most suspicious of malignant change.
If there is a history of tobacco consumption then the patient should be persuaded to stop immediately. It has been shown that if the patient stops smoking entirely for 1 year the leukoplakia will disappear in 60% of the cases.
Whenever severe epithelial dysplasia or carcinoma-in-situ is present, surgical excision or CO2 laser excision of the lesions is mandatory. Small lesions may be excised, the margins of the adjacent mucosa undermined and the defect closed by advancing the margins. For larger defects the area should be left to epithelialize spontaneously (alternatively the area can be skin-grafted). On the tongue the graft is quilted onto the raw area, whereas on the cheek, floor of the mouth or palate the graft can be retained in place by suturing a suitable pack overlying it.
When only mild to moderate epithelial dysplasia is present the patient should be followed up at 4-month intervals and details of the lesions recorded in the notes either photographically or diagrammatically.
Erythroplakia is defined as ‘any lesion of the oral mucosa that presents as bright red velvety plaques which cannot be characterized clinically or pathologically as any other recognizable condition’. Such lesions are usually irregular in outline, although clearly demarcated from adjacent normal epithelium. The surface may be nodular. In some cases erythroplakia coexists with areas of leukoplakia. The incidence of malignant change in erythroplakias is 17 times higher than that in leukoplakia. In nearly every case of erythroplakia there are areas of epithelial dysplasia, carcinoma-in-situ or invasive carcinoma. Clearly all erythroplakic areas must be completely excised, either surgically or with a CO2 laser, and the specimens submitted for careful histological examination.
In chronic hyperplastic candidiasis, dense chalky plaques of keratin are formed, the plaques being thicker and more opaque than in non-candidal leukoplakia. Such lesions are particularly common at the oral commissures, extending onto the adjacent skin of the face. In 1969 attention was drawn to the high incidence of malignant transformation in these candidal leukoplakias, suggesting that the invasive candidal infection is the cause of the leukoplakia, and not merely a superimposed infection. It has also been suggested that in such patients there may be an immunological defect which allows the Candida albicans to invade the epithelium and may render the patient susceptible to malignant change.
It is thought that treatment with antifungal agents to eliminate the candidal infection will reduce the risk of malignant change. However, treatment may be necessary for many months to eliminate the organisms and reinfection is a constant problem. Surgical excision is recommended for persistent lesions.
Oral submucous fibrosis is a progressive disease in which fibrous bands form beneath the oral mucosa. These bands progressively contract so that ultimately opening is severely limited, speech becomes hypernasal due to changes in the soft palate and swallowing is disturbed. Tongue movement may also be limited. The condition is almost entirely confined to Asians. Histologically it is characterized by jux-taepithelial fibrosis with atrophy or hyperplasia of the overlying epithelium, which also shows areas of epithelial dysplasia. Paymaster, in 1956, first discussed the precancerous nature of submucous fibrosis (see Langdon and Henk 1995). He noted the onset of a slowly growing squamous cell carcinoma in one-third of such patients. The changes are due to crosslinking of the collagen fibres caused by various alkaloids, particularly arecholine, which leach out of the arecha nut and penetrate the oral mucosa.
The scar bands of submucous fibrosis that result in difficulty in mouth opening can be treated either by intralesional injection of steroids or by surgical excision and grafting, but this has little effect in preventing the onset of squamous cell carcinoma in the generally atrophic oral mucosa. Any aetiological factors should, of course, be eliminated.
Before the antibiotic era, syphilis was an important predisposing factor in the development of oral leuko-plakia and oral cancer. The syphilitic infection produces an interstitial glossitis with an endarteritis that results in atrophy of the overlying epithelium. This atrophic epithelium appears to be more vulnerable to those irritants that cause oral cancer or oral leukoplakia. As these changes are irreversible there is no specific treatment, although active syphilis must be tre/>