Premalignancy and malignancy
Cancer manifests in various ways in the oral cavity. It is essential that dentists are able to recognise malignancy and deal with it in a professional way. Premalignant disorders are also important and the terminology used to describe them can be confusing. A rather arbitrary distinction was made in the past between premalignant conditions and premalignant lesions. These are now grouped together as ‘potentially malignant disorders’.
Previously, premalignant conditions were considered as a group of disorders associated with a small increased risk of developing oral carcinoma. The common link was thought to be epithelial atrophy, which may confer greater susceptibility to carcinogens. Atrophic epithelium has altered cell turnover rates and is likely to be more permeable. Patients with these conditions should be advised to eliminate tobacco or paan use and to limit alcohol intake, as these are risk factors for developing oral cancer.
Oral submucous fibrosis is related to using paan, which is a leaf quid containing areca nut. Many types exist, including fresh products consumed in the Indian subcontinent and southeast Asia as well as packed proprietary products. Tobacco, slaked lime, spices and other ingredients may be added; in southeast Asia, areca nuts are often chewed fresh. The mucosa and teeth become stained orange–brown because paan is held in the mouth for long periods. The affected mucosa becomes pale in colour and feels firm on palpation (Fig. 12.1). Fibrous bands may develop in the buccal mucosa and a pale, constricting fibrosis typically involves the palate. Mouth opening becomes restricted and swallowing may be difficult. The risk of developing oral carcinoma has been estimated at around 5%, although the risk of submucous fibrosis itself cannot be separated from the risks posed by carcinogenic substances in paan. In biopsy material, a subepithelial band of fine fibrillary collagen is seen in the lamina propria and the oral epithelium can be reduced to only a few cell layers in thickness. Keratinisation and chronic inflammation may be present in some cases. Where areas of erythroplasia and leukoplakia are present, biopsies may show epithelial dysplasia or even carcinoma.
Links between lichen planus and oral cancer have been debated. Some evidence links atrophic variants of oral lichen planus, characterised by red areas of mucosal thinning and erosions, with an increased tendency to develop oral cancer. There are no proven associations between oral non-erosive lichen planus or cutaneous lichen planus and malignant transformation. Lichenoid inflammation may be found in dysplastic lesions, particularly in a high-risk lesion known as proliferative verrucous leukoplakia. Other forms of lichenoid mucositis, such as lichenoid reaction and discoid lupus erythematosus, may additionally be confused with lichen planus. Tobacco or paan use should be discouraged in lichen planus sufferers. Patients should be advised to limit alcohol intake to guidelines.
A number of conditions can result in difficulty in swallowing. The association of primary iron-deficiency anaemia and difficulty in swallowing because of formation of a postcricoid fold (oesophageal web) is known as the Patterson–Kelly–Brown or Plummer–Vinson syndrome. Chronic iron deficiency results in generalised mucosal atrophy because iron is an essential growth requirement for the oral epithelium. Carcinoma may develop in the oesophagus and less commonly in the oral cavity, pharynx or larynx.
The rare disorders tylosis and dyskeratosis congenita predispose to the development of leukoplakia and oral cancer. Fanconi’s anaemia may also dispose to potentially malignant disorders and is associated with a increased risk of head and neck cancer including oral cancer.
Previously, premalignant lesions were defined as areas of morphologically altered tissue in which cancer can arise. Various terms have been used to describe these lesions and diagnosis is often made by exclusion. Many lesions do not progress to cancer and some even regress. It is probable that a proportion of lesions diagnosed as potentially malignant are actually reactive, while others do not progress within the lifetime of the patient. Discrete white or red mucosal patches are referred to leukoplakia and erythroplakia respectively. Proliferative verrucous leukoplakia (PVL) is a clinically and histologically distinctive high-risk oral lesion.
Various definitions of leukoplakia have been proposed but it is essentially a predominantly white lesion that cannot be characterised as any other definable lesion. Leukoplakia is a clinical diagnosis and has a variable histology.
• Non-homogeneous leukoplakias tend to be less circumscribed and show a greater range of appearances. Proliferative verrucous leukoplakia has a warty appearance and speckled leukoplakia has interspersed red areas. Heaping up of keratin, nodularity and ulceration may be present. The risk of malignant transformation is greater in non-homogeneous leukoplakia. Often these lesions are multifocal.
The diagnosis can only be made after careful clinical examination with representative mucosal biopsy, as these procedures are essential for exclusion of other defined disorders. A semantic problem exists in that diagnosis by exclusion may ‘lump’ more than one disease together and depends on which diseases are recognised as ‘definable’. The prevalence of leukoplakia varies from 0.2% to 4% and the risk factors are tobacco, paan, alcohol and possibly candidal infection.
The risk of malignant transformation is difficult to estimate in any individual case. Lesions in the floor of mouth and ventral tongue, and those showing evidence of epithelial dysplasia or carcinoma in situ, are considered to be at high risk (Fig. 12.2). Paradoxically, the risk of malignant transformation is greater in non-smokers than in smokers. Leukoplakia is very rare in non-smokers. The regression of leukoplakia in smokers following cessation suggests that a proportion of lesions are reactive, whereas leukoplakia in non-smokers may reflect a local cellular genetic change that tends to be progressive. However, there is evidence to suggest that smoking cessation in leukoplakia reduces risk, and an appropriate intervention is advised.
Fig. 12.2 Leukoplakia of the buccal mucosa.
Sublingual keratosis: This term is applied to leukoplakia affecting the floor of mouth and ventral tongue. One reported series described a malignant transformation in over 30% but this has not been confirmed by later studies. The term is not generally favoured because of lack of evidence supporting it as a distinct entity.
Candidal leukoplakia: It is possible for Candida pseudohyphae to invade the keratin on the surface of leukoplakia and it may cause a subepithelial chronic inflammatory response. The presence of microscopic dysplasia in this lesion causes concern. Candidal leukoplakia must be distinguished from chronic hyperplastic candidiasis which results in a firm warty or specked plaque that cannot be scraped off. It occurs most commonly on the dorsal tongue and buccal mucosa behind the angle of the mouth. Staining with diastase periodic acid-Schiff’s base (DPAS) shows pseudohyphae of Candida species growing into the keratin layer, where they are typically associated with a neutrophil inflammatory infiltrate. There is marked epithelial hyperplasia with formation of elongated and blunted rete processes. Elimination of predisposing factors such as smoking, poor denture hygiene and haematinic deficiency, combined with systemic antifungal therapy, may cause resolution of the white plaque. Reactive cellular atypia may be seen, but if dysplasia is present then the lesion must be considered to be candidal leukoplakia.
Syphilitic leukoplakia: This is less relevant to contemporary practice but carried a high risk of malignant transformation when it was prevalent. It was a complication of tertiary syphilis and tended to affect the dorsum of the tongue.
Proliferative verrucous leukoplakia (PVL): The World Health Organization classification recognises this disorder as a high-risk precursor oral lesion. Typically, multifocal mucosal lesions are identified and show a warty appearance, although flat erythematous and keratotic areas may also be present. The gingivae and palate are often affected. Microscopically there may be little cytological atypia leading to underestimation of grade pathologically. Lichenoid inflammation may further obscure recognition of dysplasia. Diagnosis is made by a combination of microscopic architectural abnormality and the clinical features. Ultimately around 80% of PVL sufferers develop oral cancer and higher grade dysplasia is frequently seen in biopsies as the disease progresses.
Erythroplakia has been defined as a bright-red velvety change on the oral mucosa that cannot be characterised as any other definable lesion. There is a high risk of transformation. Histopathologically, erythroplakia tends to show dysplasia, often in a distinctive pattern with drop-shaped rete processes, marked nuclear and cellular pleomorphism and minimal keratinisation. Carcinoma in situ is also seen often.
The term dysplasia is used in a variety of contexts in pathology and means literally ‘abnormal growth’. In the context of potentially malignant oral disorders, it refers to a combination of cytological changes and disturbances of cellular arrangements seen during the process of malignant transformation. Epithelial dysplasia is graded by oral and maxillofacial pathologists into mild, moderate and severe grades. An alternative scheme uses the term ‘squamous intraepithelial neoplasia’ (SIN 1, 2 and 3 respectively). The term carcinoma in situ is applied when abnormalities involve the entire thickness of the epithelium; in the SIN system, severe dysplasia and carcinoma in situ are combined as SIN 3. The histopathological features recognised in dysplasia are given in Table 12.1.
|Nuclear and cellular pleomorphism||Variation in the sizes and shapes of cells and nuclei|
|Increased nuclear/cytoplasmic ratio||Can be quantified using cytophotometry|
|Nuclear hyperchromatism||Intense staining of nuclei|
|Prominent nucleoli||May be larger than normal and/or increased in number|
|Abnormal mitotic activity||Increased mitotic rate, mitotic figures present above the suprabasal layer, abnormal forms|
|Basal-cell hyperplasia||Several layers of basal cells may be seen; may result in drop-shaped rete processes|
|Disturbance of basal-cell polarity||Basal cells lose their orientation; nuclei lose their polarity|
|Abnormal maturation||Loss of normal stratification pattern; maturation present at inappropriate levels|
|Aberrant keratinisation||May involve individual cells and may result in the formation of intraepithelial keratin pearls|
Studies on histopathological grading show poor kappa agreement between even specialist pathologists. This problem arises because of lack of scientific evidence for weighting the various features of dysplasia. For example, drop-shaped rete processes are generally accepted as a sinister feature, whereas increased mitotic rate may be seen in reactive processes. Both inter- and intraobserver variabilities between pathologists are high and the biological behaviour of the lesion does not always correlate with its grading. Problems may also arise because of non-representative sampling at the time of biopsy. Although histopathological grading is intrinsically unreliable, the presence of dysplasia in a suspicious lesion remains the best predictive indicator of malignant change.
The process of malignant transformation is the result of accumulation of genetic damage. There may be genomic instability or stepwise accumulation of genetic events (Fig. 12.3). The latter process is thought to operate in most oral cancers and studies have demonstrated mutations, methylation or loss of various tumour suppressor genes (e.g. p53, p16, p21, retinoblastoma, FHIT) in oral cancers. Loss of function of a tumour suppressor gene confers a selective growth advantage on the cell, resulting in an expanded population in which further genetic abnormalities are thought to arise. Abnormal oncogene activity may increase cell proliferation rates and drive malignant progression. Dysplasia is likely to represent a histopathological change resulting from genetic alterations. Aneuploidy is a change in the number of chromosomes and is being investigated as a marker of malignant change using cytology methods.
Referral to a specialist centre is usually advisable for patients presenting with white or red mucosal patches, or other suspicious lesions. Biopsy is normally required for diagnosis and to determine whether epithelial dysplasia is present. Some patients may be followed up in primary care settings.
Most oral cancers do not arise in a clinically recognised premalignant lesion and are diagnosed as primary cancerous lesions. They are typically painless, unless infected or advanced, and often cause no symptoms. For this reason, the need to conduct a careful systematic examination for every patient cannot be stressed too much. Extraoral examination should include both visual inspection of the face and neck and palpation of the neck (see Chapter 2). The patient’s head should be tilted forwards and the lymph nodes in the neck palpated in relaxed tissue. A routine technique should be adopted, perhaps starting with the submental nodes and then moving to more posterior node groups. The oral mucosa and oropharynx should be examined carefully. The tongue should be protruded to detect lateral deviation and then relaxed and lifted to allow examination of its ventral surface and the floor of the mouth. Correct positioning and the use of good illumination and mirrors are important factors. When oral cancer is detected, prompt referral is essential. The importance of attending at the hospital should be stressed, without provoking undue anxiety. Until a biopsy result is available, definitive diagnosis should be avoided. Any ulcer that fails to heal within a 3-week period should be regarded as suspicious and the patient should be referred to a specialist.
The global incidence of oral and oropharyngeal cancer has been estimated at over 405 000 new cases per year. Of these, over 30 000 occur in the USA and around 4600 occur in the UK. There is marked geographical variation in distribution, with the highest incidence in the Indian subcontinent and southeast Asia, because of the particular use of paan and tobacco. Oral and oropharyngeal cancer ranks in the top ten in prevalence tables. The incidence of oral cancer is rising and more cases are seen in younger age groups. The male to female ratio of around 2.5:1 is also changing, with an increasing oral cancer incidence in women, particularly involving the tongue.
Overall 5-year survival for oral cancer is just over 50% but depends very much on the stage at initial diagnosis and clinical factors. Squamous-cell carcinoma of the lip has a better prognosis than intraoral carcinoma. In general, prognosis is worse when tumours arise in the more posterior parts of the oral cavity than in the anterior area. Midline carcinomas in the floor of the mouth and ventral tongue may, however, spread to both sides of the neck. Staging is a system used to describe the degree of spread or tumour ‘load’ and the most widely used TNM (tumour, lymph node, metastases) system is described in Tables 12.2 and 12.3. Survival at 5 years for TNM stage I oral carcinoma is around 80%, whereas survival is reduced to 15% for stage IV. Morbidity refers to the reduction in function, both physical and psychological. Again, morbidity tends to relate to stage, as large tumours may require removal of a large amount of tissue or radical radiotherapy. Hospital readmission is frequent during treatment and, in many cases, tumours prove refractory to all forms of therapy. Quality of life can be assessed and is an important measure of morbidity. Good dental health is a significant factor.
Squamous-cell carcinoma accounts for around 95% of all oral cancers. It arises from the epithelial lining of the oral cavity. It is described in detail in the next section. A number of other forms of malignant disease also arise in the oral cavity.
Malignant melanoma: This typically occurs in the palatal and gingival mucosa. A spreading brown-pigmented patch or a raised ulcerated nodule, surrounded by pigmented mucosa, may be seen (Fig. 12.4). Prognosis is grave in nodular malignant melanoma.
Malignant lymphoma: Extranodal lymphoma arises principally in the oropharynx in the area of Waldeyer’s ring. Nodular infiltration of the mucosa is seen and lymph nodes in the neck may become involved.
Leukaemia: Leukaemia may present with oral signs such as persistent gingival haemorrhage and oral ulceration. Acute myeloid leukaemia and childhood leukaemia may cause gingival enlargement because of direct infiltration of leukaemic cells (Fig. 12.5).
Metastatic deposits: Metastasis from primary cancers in the kidney, gastrointestinal tract, lung, breast, prostate and other sites occur in the oral cavity. Often they present as gingival nodules or as destructive bone lesions. Metastatic lesions in bone are usually radiolucent, but prostate and some breast metastases appear as radio-opacities in bone.
Smoking: Cigarette smoking is the most important aetiological factor for intraoral cancer in the Western world. Risk increases with cumulative dose, which is measured in ‘pack-years’. There are no safe levels. The risk is greatest when combined with high alcohol intake. It is believed that carcinogens in tobacco smoke accumulate in the floor of the mouth, accounting for the increased risk of squamous carcinoma at that site.
Paan and other tobacco use: Paan, also known as betel quid, is used throughout the Indian subcontinent. Leaf of the betel piper vine is used to form a rolled-up quid, into which areca nut is placed. Areca is thought to contain alkaloid carcinogenic precursors. In addition, tobacco, spices and slaked lime may be added. The quid is held in the oral cavity for a considerable time and is habit forming. Buccal and labial cancers are commonly associated with paan use. Other tobacco habits exist, including smearing tobacco paste into the mouth and reverse bidi smoking, which has been linked to palatal cancer. In recent times, areca nut has become popular in southeast Asia.
Alcohol: Alcohol is an important cofactor when combined with smoking and is now regarded a risk factor in its own right. It may increase epithelial permeability, allowing greater access of carcinogenic substances to the basal cells.