12: Premalignancy and malignancy

Premalignancy and malignancy

12.1 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.

Submucous fibrosis

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.

Atrophic lichen planus

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.

Leukoplakia

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.

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.

Other terms for leukoplakia

A variety of terms have been employed to describe leukoplakic potentially malignant oral lesions.

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.

12.2 Pathology and genetics

Epithelial dysplasia and carcinoma in situ

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.

Table 12.1

Histopathological features of epithelial dysplasia

Feature Comment
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

Grading of dysplasia

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.

Tumour suppressor genes and oncogenes

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.

Management of potentially malignant oral lesions

Clinical risk factors for malignant change include tobacco habit, high alcohol intake and possibly poor diet. Clinical factors that must also be taken into account are:

Most important is the presence of dysplasia or carcinoma in situ (SIN 3). Management should include:

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.

12.3 Oral cancers

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.

Epidemiology

Morbidity and mortality

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.

Types of oral cancer

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.

Squamous-cell carcinoma

Aetiology

Jan 9, 2015 | Posted by in Oral and Maxillofacial Pathology | Comments Off on 12: Premalignancy and malignancy
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