Persistent oral ulcers and erosions can be the final common manifestation, sometimes clinically indistinguishable, of a diverse spectrum of conditions ranging from traumatic lesions, infectious diseases, systemic and local immune-mediated lesions up to neoplasms. The process of making correct diagnosis for persistent oral ulcers still represents a challenge to clinicians. Major diagnostic criteria should include the clinical appearance of both ulcer and surrounding non-ulcerated mucosa, together with the evaluation of associated signs and symptoms, such as: number (single or multiple), shape, severity of the ulcer(s), conditions of remaining mucosa (white, red or with vesiculo-bullous lesions) and systemic involvement (e.g. fever, lymphadenopathy or evaluation of haematological changes). The aim of this paper was to review the literature relating to persistent oral ulcers and provide a helpful, clinical-based diagnostic tool for recognising long-standing ulcers in clinical dental practice. The authors, therefore, suggest distinguishing simple, complex and destroying (S-C-D system) ulcerations, as each requires different diagnostic evaluations and management. This classification has arisen from studying the current English literature relating to this topic, performed using MEDLINE / PubMed / Ovid databases.
Abstract:The aim of this study is to report on the oral lesions detected in 123 patients diagnosed at the University Hospital of Bari from October 2020 to December 2020, focusing on the correlation of clinical and pathological features in order to purpose a new classification. Methods. General and specialistic anamnesis were achieved and oral examination was performed. The following data were collected: age/gender, general symptoms and form of Covid-19, presence and features of taste disorders, day of appearance of the oral lesions, type and features of oral lesions and day of beginning of therapies. If ulcerative lesions did not heal, biopsy was performed. Results. Many types of oral lesions were found and classified into four groups considering the timing of appearance and the start of the therapies. Early lesions in the initial stages of Covid-19 before the start of therapies was observed in 65.9% of the patients. In the histopathological analysis of four early lesions, thrombosis of small and middle size vessels was always noticed with necrosis of superficial tissues. Conclusion. The presence of oral lesions in early stages of Covid-19 could represent an initial sign of peripheral thrombosis, a warning sign of possible evolution to severe illness. This suggests that anticoagulant therapies should start as soon as possible.Keywords: Covid-19; oral lesions; oral ulcers; classification
Further to these concerns, we know that premalignant conditions tend to develop in what is known as field change. This means that for any subsite within the oral cavity at which cellular nuclear damage resulted in a PMD (or even cancer), the adjacent mucosa is almost equally at risk of producing additional PMD lesions even if they appear normal to the naked eye.
It is important to note that a role for primary prevention in patients with leukoplakia is not confirmed. For example, smoking is a risk factor for the development of leukoplakia, but smoking cessation does not necessarily reduce the risk of developing OCC. There is, however, benefit in screening for potentially malignant lesions, and this was demonstrated in a recent review of the US SEER-Medicare database of head and neck cancer. Yanik et al.  reported better treatment and survival outcomes in patients who developed oral cell carcinoma whilst under follow-up for a premalignant lesion . This correlated with the fact that oral cancers were identified at an earlier stage in this patient cohort. Patients without the benefit of such close observation tended to present with more developed or advanced tumour forms. A role for screening patients following treatment for head and neck cancer recurrence is not known, and thus secondary prevention is not currently known to be effective. It is likely, however, that the principle of recognising early tumours and potentially malignant lesions would still result in timely provision of therapy. Table 80.1 enlists premalignant lesions discussed in this chapter.
With each cell division, there is a probability of errors arising in the nuclear DNA resulting in a defective daughter cell. Most errors are corrected during cell division, or the cells are removed by immune mechanisms. Defective cells that have escaped these reparative measures may still be suppressed by transcription factors that induce apoptosis. Apoptosis is triggered through p53, a tumour suppressor protein. The protein p14 is an alternative reading frame of the CDKN2A gene responsible for initiating the p53 pathway. Direct degradation of p53 by the E6 viral protein (HPV-related cancer) or genetic mutations in the parent gene (in 60% of non HPV cancer) restricts protective physiological apoptosis leading to a shift in cell population and accumulation of dysplastic cells. The premise behind looking out for premalignant disorders is that oral mucosa will change appearance with the onset of dysplastic changes and that the extent of dysplasia does correlate with malignant potential. High-grade dysplastic lesions indicate treatment is required imminently, whereas mild dysplastic lesions may be observed and are even considered a feature of benign chronic inflammation. Dysplasia is classified according to several grading systems summarised in Table 80.3, the most common system in use being the one proposed by the WHO in 2005. Further genetic changes are involved in progression towards invasiveness, but these are not as well defined as these are outside the scope of the chapter.
Clinical variants of leukoplakia include homogenous plaques, nodules, speckled erythroleukoplakia and a distinct subtype discussed separately: proliferative verrucous subtype. Leukoplakia is present in less than 1% of the general population  but with greater prevalence reported among those older than 75 years of age and tobacco users of all age groups . Men are twice as much likely to develop leukoplakia compared with women. In the Indian subcontinent, in regions where betel is consumed, prevalence rates approach 5% . The annual risk of malignant transformation is estimated between 1 and 2% . Larger non-homogeneous lesions, particularly those on the tongue and floor of the mouth, are associated with the highest conversion rates to oral squamous cell carcinoma. Table 80.5 lists clinical risk predictors for malignant transformation.
Tissue biopsy is required to assess the degree of epithelial dysplasia, an independent and consistently reliable risk factor for malignant transformation. Liu et al., using a binary grading of dysplasia, found that patients with high-risk lesions (moderate/severe dysplasia) eight times as likely to be diagnosed with oral cancer as those with low-risk (no/mild dysplasia) lesions . Histological evaluation may also identify other conditions that are clinically indistinguishable from idiopathic leukoplakia such as hyperplastic candidosis, oral lichen planus variants, lichenoid reactions and discoid lupus.
Medical treatments for oral premalignancy include systemic vitamin A, systemic beta carotene and topical bleomycin. These were shown to control premalignant lesions, but a 2016 Cochrane review concluded that relapse rates were high and that transformation into oral cancer was not effectively reduced .
Erythroplastic lesions (Fig. 80.3) are similarly defined to oral leukoplakia but as red velvety lesions following exclusion of other named entities. It is a rare disorder with prevalence between 0.01 and 0.2% but a much higher transformation rate compared to leukoplakia, reportedly between 51 and 90% . Clinical appearance tends to follow one of three patterns: the homogenous, granular and speckled types . Most common subsides are the palate, the buccal mucosa and the floor of the mouth. Lesions are rarely multicentric and may present a similar clinical appearance to erosive and atrophic oral lichen planus, erythema migrans, stomatitis, candidosis, lymphatic malformations and desquamative gingivitis (e.g. vesiculobullous lesions and gingival lichen planus). Speckled erythroplakia and leukoplakia most likely refer to the same disorder with red appearance correlating to high-risk epithelial dysplasia. Treatment options are surgical excision, laser excision or evaporation as per leukoplakia with a lower threshold for application for wide local excision due to the higher risk of cancer development.
It is not clear whether oral lichen planus (OLP), a relatively common benign condition, is an independent risk factor for malignancy. A meta-analysis of 7806 patients concluded that just over 1% of patients OLP develop oral cavity cancer . The highest risk subsites were predominantly the tongue (51%) and the buccal mucosa (32%). Malignant transformation was three times as likely in females as it was in men. It is proposed that changes at lower-power magnification of oral leukoplakia resemble lichen planus or that lichenoid changes in epithelial dysplasia are common. Clinically, there is overlap between the clinical appearance of the various types of OLP and between erythroleukoplakia and verrucous leukoplakia. A diagnosis of OLP is more likely in symmetric lesions, but only a biopsy demonstrating epithelial dysplasia would confirm truly high-risk lesions. Correlation between malignant change and certain subtypes of OLP, namely, the erosive and plaque-like forms, has not been consistent. Interestingly a co-existence with proliferative verrucous leukoplakia has been noted by several authors [25, 26].
Candida is present in the oral cavity in between 40 and 60% of healthy individuals. Association between Candida infection and cancer is through smoking, an independent risk factor equally for the development of chronic hyperplastic candidosis (CHC) and premalignant mucosal lesions. Once hyperplastic candidosis is established, these lesions manifest and behave similar to homogeneous or speckled leukoplakia with 15% risk of progression to epithelial dysplasia . CHC is usually resistant to antifungal therapy, and thus surgery is indicated particularly for well-defined lesions. 2b1af7f3a8