Potentially malignant lesions of the oral mucosa (precancerous lesions, premalignant lesions, oral potentially malignant disorders – OPMD) are clinical manifestations bearing risk of turning into malignant proliferation in the oral cavity. The current WHO classification from 2017 classifies all types of such lesions into a single group (Table 1) and thus disregards the former attempts to classify the diseases according to their susceptibility towards malignant transformation or relationship to systemic diseases (Slootweg et al., 2017). A separate class was created for proliferative verrucous leukoplakia, which is a particularly aggressive type of OPMD and has an especially high potential to malignant transformation and capability to recur.
|Oral submucous fibrosis
|Chronic hyperplastic candidosis
|Oral lichen planus – atrophic and erosive forms
|Discoid lupus erythematosus - atrophic and erosive form
|Sideropenic dysphagia (Patterson-Kelly, Plummer-Vinson syndromes)
The prevalence of oral leukoplakia in the western countries ranges from 1 % do 4 %; in some parts of Southeast Asia, even higher prevalence is reported (Napier a Speight, 2008). Oral erythroplakia is, on the other hand, a rare lesion with prevalence between 0.02 % and 0.83 % (Reichart, 2005). Males are affected more often than females.
OPMDs arise due to various etiologies. The tobacco abuse (smoking and/or chewing) and alcohol consumption are among the most prominent factors associated with the development of leukoplakia (Napier a Speight, 2008). For most OPMDs, however, etiological factors are unknown. The influence of human papillomavirus (HPV) infection on the development of OPMDs is discussed in the Chapter 5.3.6.
OPMDs can occur anywhere on the oral mucosa. The site of the lesions usually depends on the particular etiological factor (Napier a Speight, 2008). Erythroplakia is more common on the soft palate, oral floor and buccal mucosa (Reichart a Philipsen, 2005).
Most high-risk OPMDs are represented by white, red or spotted oral lesions. They can be homogenously white or mostly white with a nodular, verrucous or erythematous area.
OPMDs occur in rare syndromes such as Fanconi anaemia (Cavalcanti et al., 2015) or dyskeratosis congenita (Handley et al., 2006); nevertheless, most cases develop without any known genetic predisposition.
Prognosis and prediction factors
Although the presence of dysplasia in the lesion correlates with the probability of development of the squamous cell (spinocellular, squamocellular) carcinoma, most OEDs never turn malignant. A general rule is that a higher degree of dysplasia correlates with a higher probability of developing carcinoma (Mehanna et al., 2009, Silverman et al., 1984).
Oral epithelial dysplasia (OED)
The term OPMD describes all pathological processes that do not represent carcinoma on themselves but under certain circumstances, they can turn malignant. Such lesions can show a wide range of changes in the cytology and architecture of the epithelium and be associated with an increased risk of malignant transformation. Those changes are termed oral epithelial dysplasia (OED). Dysplastic changes are found in most erythroplakias and erythroleukoplakias while in leukoplakia, the rate of dysplasia is significantly smaller. Histological changes associated with histological criteria of epithelial dysplasia are summarized in the Table 2.
|Changes in the tissue architecture
Irregular epithelial stratification, loss of normal epithelial maturation
Nuclear and cellular pleomorphism (anisocaryosis, anisocytosis)
Loss of basal cell polarity
Teardrop-shaped rete ridges
Higher frequency of mitosis
Increased nuclei with irregular contours
Mitosis outside the basal epithelial layer, i.e, in the upper layers of the epithelium
Increase of the N/C ratio
Dyskeratosis – premature keratinization in individual cells
Keratin pearls in the rete ridges
Increased number and size of the nucleoli
Loss of cohesion of the epithelial cells
Hyperchromasia of the nuclei, coarser chromatin structure
OED is classified according to the severity into three tiers, taking into account the number of the “thirds” of the affected epithelium. In mild dysplasia, the atypical cells are limited to the basal membrane, moderate dysplasia affects also the medium third and severe dysplasia also the uppermost third of the epithelium (Slootweg et al., 2017), see Table 3. Recently, a binary two-tier grading system, distinguishing only between low-grade and high-grade dysplasia, is becoming preferred.
|WHO classification 2017
Mucosal lesions of the character of carcinoma in situ of the oral mucosa (i.e., intraepithelial carcinoma) that is limited to the epithelium only and does not extend beyond the basal membrane) is at present classified as severe dysplasia (Slootweg et al., 2017).
The clinical descriptive term leukoplakia can, according to the macroscopic picture, encompass various clinical conditions, the common feature of which is a “white area“ (leukos = white). Several definitions of the term leukoplakia have been proposed, corresponding to the state of knowledge at the time of creating the definition. The World Health Organization (WHO) originally defined leukoplakia as a white area that cannot be characterized clinically or histopathologically as another disease. The next step was the exclusion of keratoses (frictional keratosis and smoker’s leukokeratosis) that generally count among benign lesions and have a tendency to regress after removal of the source of local irritation. The clinical differentiation of such lesions is however difficult and can only be reliably established based on histopathological examination. One of the most recent leukoplakia definition proposals reads: leukoplakia is a predominantly white lesion of the oral mucosa that cannot be histologically or histopathologically classified as another lesion and that is associated with the increased risk of the development of carcinoma in the region of the lesion, elsewhere in the oral cavity or in the region of the head and neck (Isaäc van der Waal, 2015).
A definite diagnosis of oral leukoplakia can be only established after an evaluation of the macroscopic finding, considering possible etiological factors, and, in particular, histological examination. Leukoplakia in a more general sense relates to increased keratinization of the mucosa that are under normal circumstances covered by a non-keratinizing squamous epithelium. White spots can develop anywhere on the mucosa with predilection towards buccal mucosa. Generally, several types of leukoplakia can be distinguished: homogenous – lesions are white, with a smooth or furrowed surface, and non-homogenous – with verrucous, nodular, ulcerative character or characteristics of erythroplakia/erythroleukoplakia.
Various possible etiologies of leukoplakia are known, the etiological factors in particular include various irritant factors inducing a chronic inflammation and potentially participating in the development of carcinoma that the leukoplakia can turn into. Such factors include mechanical effects (carious teeth, unsuitable prosthetic devices, traumatising the buccal mucosa by biting, etc.), chemical, eletrogalvanic and actinic factors. Those include in particular tobacco abuse – effects of smoking. Males between 40 and 60 years of age are the most affected group. The malignant transformation of leukoplakia occurs in 3-6 % of cases. For initiation of the tumour growth, a serious accumulation of factors is needed, such as a combination of local irritation, systemic factors, and the susceptibility of the organism. Non-homogenous leukoplakias are more associated with malignant transformation that homogenous ones, in particular verrucous and erosive leukoplakias (up to 30 % of erosive form turns malignant).
Histology: Keratosis, hyperkeratosis and/or acanthosis are often found. In some leukoplakias, dysplastic changes are present, see Table 2.
Th.: Any leukoplakia needs histopathological verification. The ways of treatment differ according to the clinical and histopathological picture. In simple hyperkeratosis (frictional keratosis, smoker’s leukokeratosis), simple removal of the irritant factors and smoking cessation are often sufficient and the lesion regresses spontaneously over time. It is however still necessary to perform regular (half-year) follow-ups of the leukoplakia lesions and if the lesion persists, to perform biopsy. A radical surgery is indicated in non-homogeneous forms with a high risk of malignant transformation, in particular where epithelial dysplasia is present in the tissue removed during (incisional or excisional) biopsy.
Dif. dg.: Oral leukoplakia must be distinguished from so-called „hairy leukoplakia“, which is a manifestation of EBV, affects in particular HIV-positive patients and occurs in particular on the sides of the tongue.
This exophytic proliferative leukoplakia with papillomatous or cauliflower-like appearance affects in particular the buccal mucosa, palate and lingual mucosa. Histopathologically, a hyperkeratosis without or only with minimum representation of dysplasia is observed. The definitive diagnosis is established based on both the clinical appearance and histopathological examination. It has a marked tendency to recur (up to 70 %) and to transformation into verrucous carcinoma (Slootweg et al., 2017).
The appearance of erythroplakia is that of a fiery red area on the oral mucosa. Usually, it is well circumscribed with satin appearance and without indurations. In histological examination, high grade dysplasia is often present, indicating a high risk of possible tumour development.
Th.: Radical surgical therapy.
Dif. dg.: Differential diagnosis from chronic erythematous candidosis is sometimes difficult. In candidosis, the erythematous area of the mucosa (usually on the palatal or lingual dorsal mucosa) is on the same level as the surrounding mucosa. Erythroplakia however usually does not occur at those sites. Atrophic OLP is also difficult to differentiate from erythroplakia – up to 1 % of OLP cases are associated with simultaneous erythroplakia (it is necessary to perform biopsy!).
White lesions with red patches are called erythroleukoplakia (also erosive or speckled leukoplakia). Histological examination often reveals the presence of dysplasia. The risk of its development is increased by alcohol and tobacco abuse (both smoking and chewing).
Th: Radical surgical therapy
This disease occurs in South Asia but can also develop in Asians living in Europe. It is caused by chewing tobacco and areca nuts (often in combination with betel leaves). The alkaloids contained in these materials stimulate the production of collagen fibres that are relatively resistant to collagenase action. The generalized fibrosis of soft tissues can cause trismus, lip rigidity and limited mobility of the tongue. Reports indicate that 7-13 % of the oral submucosal fibrosis turns malignant. Treatment relies on cessation of betel and areca nuts chewing, rehabilitation of mouth opening and application of corticoids into the affected area. Tissue changes are however irreversible.
This rare congenital disease is characterised by a triad of symptoms: pigmentations on the skin, nail dystrophy, and leukoplakia lesions in the oral cavity. In extensive lesions where the surgical treatment is contraindicated, corticoids can be locally administered.
This relatively rare form of oral candidosis occurs in particular in immunodeficient patients, especially in middle-aged or elderly. Most patients are smokers. Chronic lesions of this disease gradually change from translucent, palpable white areas into large, lustreless, dense plaques. The homogenous form is characterized by the presence of continuous white plaque while the nodular form forms multiple white “knots” under which erythematous lesions develop; the “knots” can however be neither brushed away nor torn down. The buccal mucosa, palate and tongue are most commonly affected. This candidosis represents an invasive form, with hyphae invading deep into the mucosa. Its appearance is similar to that of leukoplakia, it can progress and undergo malignant transformation. (Fidel et al., 2005).
See Chapter 6.1.3. Malignant transformation in these forms are observed approximately in 3 % of patients.
See Chapter 6.1.2. Development of carcinoma has been reported in the atrophic epithelium (especially of the lower lip).
See Chapter 6.1.2. It is a well-known fact that individuals suffering with some forms of this rare blister-forming diseases bear higher risk of development of spinocellular carcinoma.
See Chapter 5.4.3.
See Chapter 5.1.4.
It affects in particular middle-aged women with lack of Fe in the blood serum (See Chapter 6.2.1). The entire oral mucosa is glossy, red and atrophic. Development of leukoplakias is quite common and may lay a base for malignant transformation (in particular in the rear part of the oral cavity and in the orolarynx).