The global incidence of oral cancer is currently 500,000 new cases every year, of which approximately 3% are malignant, and thus constituting a world health problem. [1] Of the malignant conditions squamous cell carcinoma accounts for approximately 95% of all oral cancers. [2] Oral cancer has a tendency towards late-state detection, which is deleterious for the patient given its high fatality rate. Thus, early detection of oral cancer is essential to reduce the consequences of this disease and help improve the survival prospects of patients .[1] In 2005, the World Health Organization changed the classification, terminology, and definition of oral lesions that are considered premalignant, instead using the term ‘potentially malignant disorders.’[3] Potentially malignant oral disorders are conditions and lesions that have a high risk of malignant transformation into oral squamous cell carcinoma. [4] Oral leukoplakia, oral erythroplakia, and oral submucous fibrosis are the most common premalignant lesions. [3] The malignant incidence of oral leukoplakia and oral erythroplakia is influenced by other factors, such as aetiological factors, size and location; for example, the lateral border of the tongue and the floor of the mouth have been linked with the highest percentages of malignant transformation. [4] An example of the three most frequent pre-malignant conditions can be seen in Figure 1.

Figure 1: Clinical photographs illustrating the three most common “potentially malignant conditions” - Oral leukoplakia (left), oral erythroplakia, (middle) and oral submucous fibrosis (right). (Sourced from the web)

Assessment

Presenting Complaint And History

Assessment of oral lesions must include the history of the lesion itself, a full medical history, clinical and radiographical examination (if appropriate), and any laboratory tests that are deemed necessary. Those steps help guide the practitioner and hopefully lead to a narrower differential diagnosis, informing the decision to undertake a biopsy and leading to appropriate treatment decisions. [5] In general a through history and examination is essential to determine the most likely diagnosis. The patient should thus be asked how long the lesion has been there, as this may indicate whether it is something benign or malignant. In addition, questioning and examination must determine whether the size of the lesion has changed, as a lesion that grows aggressively may indicate a malignancy, while a static or slow growing lesion would suggest a benign lesion. Questioning whether the lesion has changed in character, for example, a lump becoming an ulcer, also assists in diagnosis [5].

Symptoms

Importantly, symptoms that are associated with the lesion, such as pain, discomfort, tissue mobility, alteration in function, anaesthesia or paraesthesia, and abnormal taste or odour, must be discussed and evaluated. Details about the symptoms should be discussed further, including whether the pain is acute or chronic, [5] or whether the patient experiences sensory changes, such as numbness or tingling of the surrounding area, both of which can be associated with malignancy or inflammation. The anatomical location also provides clues for a potential diagnosis, as each variety of lesion is associated with or has a higher propensity for a specific location. [5] The patient should also be asked whether the lesion is associated with or has coincided with any systemic symptoms, as many viral conditions (e.g., measles, mumps, and herpes) may manifest orally, and other oral ulcerative manifestations (e.g., pemphigus, lichen planus, and sexually transmitted infections) may present elsewhere in the body.[5] Furthermore, the patient should be asked whether any related event was associated with the onset of the lesion (e.g., trauma, recent treatment, or exposure to toxins. [5] Common oral and perioral lesions could be attributed to bad habits, hard or hot foods, applying medication that is not for topical use, or a dental condition (e.g., caries, periodontal disease, restorations or ill-fitting dentures) [5].

Medical Status

As part of the overall assessment the medical status of the patient should be determined. In recent years evidence has demonstrated that there can be a relationship between a patients’ medical and dental health, and any pre-existing health conditions that may alter or be altered by dental treatments or interventions should be discussed. These include but are not limited to cardiovascular disease, respiratory disease, hepatic or renal deficiencies, gastrointestinal problems, haematological dyscrasias, diabetes, immunocompromised patients or even a general inability to withstand surgical interventions. [5] These enquiries may reveal that the lesion is a manifestation of a systemic condition; for example, a chronic asthmatic patient may well have oral candidiasis due to long term use of steroid inhalers. This is one of many examples.

Social History

As a clinician you should also enquire about the patients social history and habits as this may have a significant bearing on the condition of the oral mucosa and soft tissues (e.g., age, occupation, smoking, and alcohol consumption. [2] For example, the incidence of oral leukoplakia is directly correlated to the recreational use of tobacco for smoking and chewing. [6] Additionally, any surface ulceration in chronic smokers may indicate the possibility of oro-pharyngeal cancer, and thus a relationship between social history and oral health must be established. [5] Smoking is one of the main risk factors that contributes to oral mucosal lesions such as leukoplakia, because cigarettes contain numerous chemical compounds and free radicals, such as nicotine, ammonia, carbon monoxide, formaldehyde, hydrogen sulphide and arsenic, many of which can cause cellular damage and know to be oncogenic. [7]Alcohol consumption is also considered a local and systemic risk factor for oral cancer, as it increases the permeability of oral mucosa and reduces the lipid content of the epithelium, which causes epithelial atrophy and interference in DNA synthesis and repair. [8] Alcohol also decreases salivary secretion because of its genotoxicity and mutagenic effects. Additionally, it effects the liver’s ability to dispose of toxic or potentially carcinogenic components [8].

Clinical Examination

A thorough clinical examination should then follow making sure to examine all the regions of the oral cavity. The lesion should be assessed in terms of its site, extent, texture, and colour to promptly detect a potentially cancerous lesions.[9] Manual palpation is also important, as it provides information about the uniformity, consistency and invasiveness of the lesion which may indicate the potential for malignancy. [9] Clinical examination of the lesion includes evaluation of its physical characteristics, such as whether the lesion is flat, nodular, pedunculated or ulcerated, is single or multiple, has a smooth or irregular surface, its size, shape, and growth pattern (either endophytic or exophytic from the epithelial), coloration, consistency, (whether firm or indurated, soft or compressible) and the presence of pulsation (which may indicate a vascular component). [5] In this case the buccal mucosa, gingiva, floor of the mouth, all borders of the tongue and lingual corridors should be examined both visually and by palpation. Mobility of the tongue and floor of the mouth should also be assessed to assess swelling, fixation or any expansion. [10] The clinical examination might also include a screening program for the detection of a premalignant lesion, such as visual screening, visual staining by toluidine blue, or light-based techniques, [11] however, because these tests are based on subjective interpretation, they are often considered unreliable. [12 ]Light-based techniques such as chemiluminescence and auto-fluorescent imaging are also used to detect neoplastic changes. These tests are based on the assumption that neoplastic and pre-neoplastic tissues that have gone through metabolic and structural changes have different absorbance and reflectance characteristics compared to normal tissues when exposed to specific wavelengths of light. [13] However, none of these screening programs have surpassed visual examination although there is insufficient evidence to either recommend or disprove the use of these techniques as an adjunct to visual examination [11].

Special Investigations

Following a provisional diagnosis, it may be beneficial to undertake specific special investigations to help obtain a definitive diagnosis, as this will influence what treatment will be required for the patient. Firstly, a biopsy will be required as this will help determine the cell type associated with the lesion and whether there are any sinister features associated with the tissue sampled. These may include evidence of cellular atypia such as increased nuclear size, variation in nuclear or cell size (pleomorphism), lack of differentiation (anaplasia), increased nuclear DNA content (hyperchromatism), prominent nucleoli or irregular chromatin distribution within nuclei and evidence of increased mitoses, or tissue invasion, which may demonstrate a breach of the basal layer of the mucosa and invasion into surrounding tissue.

There are several types of biopsy and these include – brush, incisional and excisional biopsy. Oral trans-epithelial brush biopsies are used to differentiate between normal, pre-cancerous and cancerous lesions, and although quick and simple to undertake the disadvantage is that often the results are questionable or inclusive, and specialist training is required to interpret the specimens. Although they may not be the preferred method for obtaining a first diagnosis they can be used as a follow-up tool. [12] The second type of biopsy is an incisional biopsy. This is usually used with lesions that are larger than 1 cm in any one dimension or with multiple, diffuse, or suspected malignancies. [14] The sample taken should be representative, deep and narrow with a depth of approximately three times the width. [14] It has also been suggested that when the lesion includes an area containing leukoplakia or erythroplakia, multiple samples should be taken, and if this is not possible then area with erythroplakia should be prioritized as it is likely involving the higher levels of cellular atypia. [14] However, incisional biopsies do carry a risk of under diagnosis, as the sample taken may not be “truly” representative of the lesion as a whole. [15] The third type of biopsy is an excisional biopsy, which is performed for innocent lesions that can be treated through complete removal: that is, lesions smaller than 1 cm, clinically suspected to be benign, and surgically accessible. Furthermore, removal of the lesion must include a clear margin of normal tissue. [14] Excisional biopsy with margin control is useful in both the diagnosis and treatment of oral cancers in specific instances. [16] However, it carries the disadvantage of overtreatment: excessive normal tissue is removed with potentially benign lesions to guarantee a sufficient margin in case of malignancy; in contrast a strict margin around a lesion which could prove malignant would then require additional surgery. [17] Clinical examination alone is insufficient to diagnose leukoplakia: for the diagnosis of oral cancer and premalignant lesions, biopsy and histopathological examination are considered the “gold standard.” [18,19].

However, there are several relative contra-indications including; 1) seriously ill patients (systemic disorders that may get worsen by attempting biopsy), 2) patients with a suspected vascular lesion or unstable coagulopathy with a risk of massive and persistent bleeding and 3) patients for whom the clinical diagnosis is an anatomical variant such as gingival pigmentation, geographic tongue, or Fordyce granules. [14] In this specific case it would be appropriate to undertake an incisional biopsy to obtain a definitive diagnosis and if the lesion was large (>2cm) to take multiple samples to increase the chance of obtaining a representative sample. Radiographical examination may also be appropriate it is thought adjacent structures including bone may be involved. Radiographs can be used to identify how near the lesion is to other anatomical features, as well as to aid in treatment planning. Computer tomography (CT) or magnetic resonance imaging (MRI) may also be considered useful to assess the extent of any lesion and if there is evidence or anticipation of loco-regional spread and involvement of adjacent soft tissue including the skull base, pharynx, neck and lymphatics. [10,20] CT an MRI are both used as locative imaging tools that visualizes the lesion in three dimensions and shows its relationship to other structures, however, whilst CT has superior for hard tissue assessment, MRI has superior soft tissue resolution. [10] In this particular patient an OPT radiograph or CT scan may be appropriate id there is evidence of bony association or involvement on the lingua aspect of the mandible. However, if a biopsy subsequently confirms a malignant lesion then a CT or MRI of the floor of mouth, tongue and neck may be more appropriate.

When trying to obtain a diagnosis a clear, concise and methodical approach to characterising and assessing any lesions (soft or hard) will help to obtain a differential diagnosis. The illustration below highlights a systematic approach to obtaining such a diagnosis. (Figure 2).

Figure 2: An illustration of a systematic approach to determining a differential diagnosis (Sourced from the web)

Further considerations can also be given to the specific characteristics of the lesion itself and this may lead you to a more specific diagnosis. However, as detailed above, this would need to be confirmed by undertaking a biopsy (Figure 3).

Figure 3: A flow diagram highlighting the process of obtaining a definitive diagnosis of an intra-oral soft tissue lesion (Sourced from the web)

Considerations For Leukoplakia/Erythroplakia

Oral leukoplakia is described by the World Health Organization (WHO) as ‘a white plaque of questionable risk’ at which a diagnosis arrives ‘having excluded other known diseases or disorders that carry no risk’. The lesion has two main recognized clinical variants: homogenous and non-homogenous leukoplakia.[4]Erythroleukoplakia is the non-homogeneous leukoplakia, which is a predominantly white or white-and-red lesion with irregular texture that may contain ulceration and is characterized by either speckled, nodular, or verrucous topography.[21] The second type is the homogeneous oral leukoplakia, which is a thin, flat, uniform white area that may alternate with normal mucosa. [22].

Oral leukoplakia occurs in approximately 1% of the population and occurs predominantly between the fifth and seventh decades of life and is six times more common in smokers. Additionally, alcohol consumption is an independent risk factor.[23] Its prevalence ranges from 1-5% of oral lesions, with a rate of possible malignant transformation from 3 - 17%. The buccal mucosa, tongue, floor of the mouth, gingivae and lower lip are the most commonly affected sites, with leukoplakias on the soft palate, ventro-lateral aspects of the tongue & the floor of mouth having the highest risk of malignant transformation. The primary risk factors include smoking and alcohol consumption with size and duration of lesion, lesion on the floor of the mouth or lateral of the tongue and the presence of candida albican having additional influence on malignant transformation.[21] Oral erythroplakia is described morphologically as a red, velvety plaque or patch that cannot be classified using any pathophysiologic process with the exclusion of all diagnosis. Furthermore, it can occur alone or in association with leukoplakia, in which case it is diagnosed as erythroleukoplakia.[19]

Histologically, oral leukoplakia is classified as a “safe lesion” unless there are signs of cellular atypia or local invasion (see comments before) which may indicate either dysplasia, carcinoma-in-situ or frank neoplasia. The presence of dysplasia indicates the risk of oral cancer.[12] Dysplasia is defined as an architectural disturbance accompanied by cytological atypia (the changing shape and size of keratinocytes) and can be mild, moderate, or severe based on features of the biopsy that are either prominent or numerous. In addition to the characteristics detailed previously these may include irregular epithelial stratification, loss of polarity of basal cells, increased number of mitotic figures, keratin pearls, pre-mature keratinization in single cells, and abnormally superficial mitosis.[24] The presence of epithelial dysplasia has historically been considered the strongest indicator of possible malignant transformation; however, some now advocate that it is safe and appropriate to treat all leukoplakias regardless of dysplasia presence [22,25].

Management

After histological confirmation of the diagnosis is obtained through the biopsy, surgical treatment may be appropriate. In addition to the histological characteristics (normal vs abnormal characteristics) this may depend on the size, duration, site and the presence of any risk factors. In all cases the main aim of management is to detect and avoid malignant transformation. [21,22] Numerous approaches have been proposed to manage leukoplakia, including surgical excision using various techniques (scalpel, cryosurgery, photodynamic therapy, laser surgery, and vaporization), medical treatment discontinuation of risk activities (smoking and alcohol consumption), and no treatment accompanied by strict monitoring. [21] If the epithelial dysplasia is moderate to severe, surgical treatment is recommended. [26] If the lesion is small and demonstrates a normal histological appearance and there are no risk factors, it may be appropriate to review the patient at regular intervals. However, if the lesion is large, and demonstrates histological characteristics of atypical cellular behaviour and risk factors are present and persistent then surgical intervention may be appropriate. If this is the case the laser excision/ablation may be appropriate. However, if features of malignancy were determined then a prompt referral to Head and Neck multidisciplinary team would be appropriate to determine the most suitable course of action. The purpose of surgical excision is clinically removing the affected tissue, which may prevent the development of oral cancer. [21] Conventional surgery includes excision or ablation of the lesion. [12] Laser surgery brings the advantages of controlling hemorrhaging both during and after the procedure and causing minimal damage to adjacent tissue, thus reducing acute inflammation, postoperative pain, swelling, and edema. Additionally, laser surgery produces excellent healing with limited scarring and contraction. [27] However, laser surgery can cause a delay in epithelial regeneration, and a granuloma may form on the wound surface. [27] Both electrocoagulation and cryosurgery cause postoperative pain and oedema and the evidence for effectively dealing with dysplastic changes is questionable. [12] Alternative therapies such as medical and complementary treatments such as Vitamin A and b-carotene are proven to be effective in the short term in some studies, there remains a high risk of relapse. [21] Finally, even with effective treatment lifelong follow-up examinations every 6–12 month may be required for those patients with more progressive lesions, [28] and these should include a careful clinical examination, and biopsy if any changes occur. Additionally, the patient should be taught how to perform self-examination. [29]

Conclusion

Managing oral premalignant lesions is considered challenging for every dental practitioner or specialist. However, obtaining a differential diagnosing in a structured and methodical way; this can be achieved by a full investigation of a patient’s presenting complaint, history of the lesion, medical history and lifestyle, is of utmost importance. Furthermore, a thorough clinical examination and biopsy are essential for obtaining a definitive diagnosis. Management can vary and be dependent on the specific presentation of the case however, surgical removal is the most appropriate treatment if there is suggestion that malignant transformation is a strong possibility, as the effectiveness of medical and complementary treatments remains unreliable.

References

1. Messadi DV (2013) Diagnostic aids for detection of oral precancerous conditions. International Journal of Oral Science 5: 59-65.
2. Theaker ED, Horner K, Sloan P, Coulthard P (2013) Master Dentistry. Third ed. Great Britain: Elsevier Ltd 367.
3. Yardimci G, Kutlubay Z, Engin B, Tuzun Y (2013) Precancerous lesions of oral mucosa. World Journal of Clinical Cases. 2: 866-872.
4. Farah CS, Woo S-b, Zain RB, Sklavounou A, McCullough MJ, Lingen M (2014) Oral Cancer and Oral Potentially Malignant Disorders. Int J Dent 2014: 853479.
5. Hupp J, EllisIII E, R.Tucker M. CONTEMPORARY ORAL AND MAXILLOFACIAL SURGERY. SIXTH ed. 3251 Riverport Lane
6. Louis, Missouri 63043: Elsevier Inc.; 2014. 704 p.
7. Lodi G, Porter S (2008) Management of potentially malignant disorders: evidence and critique. J Oral Pathol Med. 37:63-69.
8. Ahmadi-Motamayel F, Falsafi P, Hayati Z, Rezaei F, Poorolajal J (2013) Prevalence of Oral Mucosal Lesions in Male Smokers and Nonsmokers. Chonnam Medical Journal. 49 :65-68.
9. Rivera C (2015) Essentials of oral cancer. International Journal of Clinical and Experimental Pathology. 811884-11894.
10. Waal Ivd (2016) Atlas of Oral Diseases: Springer Berlin Heidelberg 2016.
11. Andersson L, Kahnberg K-E, Pogrel MA (2010) Oral and Maxillofacial Surgery. United Kingdom: Blackwell Publishing Ltd 1312.
12. Brocklehurst P, Kujan O, O'Malley LA, Ogden G, Shepherd S, Glenny A-M ( 2013) Screening programmes for the early detection and prevention of oral cancer. Cochrane Database of Systematic Reviews. 2013(11).
13. Kumar A, Cascarini L, McCaul JA, Kerawala CJ, Coombes D, Godden D (2013) How should we manage oral leukoplakia? British Journal of Oral and Maxillofacial Surgery. 51:377-383.
14. Nagi R, Reddy-Kantharaj Y-B, Rakesh N, Janardhan-Reddy S, Sahu S (2016) Efficacy of light based detection systems for early detection of oral cancer and oral potentially malignant disorders: Systematic review. Medicina oral, patologia oral y cirugia bucal. 21:e447-e55.
15. Chan MH, Wolf JC (2012) Biopsy Techniques and Diagnoses & Treatment of Mucocutaneous Lesions. Dental Clinics of North America. 56(1):43-73.
16. Pentenero M, Carrozzo M, Pagano M, Galliano D, Broccoletti R, Scully C, Gandolfo S (2003) Oral mucosal dysplastic lesions and early squamous cell carcinomas: underdiagnosis from incisional biopsy. Oral Diseases. 9:68-72.
17. Wang YC, Fang KH, Jung SM, Zheng J, Hao SP (2010) Excisional biopsy with margin control for oral cancers. Head & Neck. 32:1528-1533.
18. Jeong WJ, Paik JH, Cho SW, Sung MW, Kim KH, Ahn SH (2012) Excisional biopsy for management of lateral tongue leukoplakia. Journal of Oral Pathology & Medicine. 41:384-388.
19. Mutalik S, Mutalik VS, Pai KM, Naikmasur VG, Phaik KS (2014) Oral Leukoplakia – Is Biopsy at the Initial Appointment a Must? Journal of clinical and diagnostic research : JCDR. 8:ZC04-ZC7.
20. Awadallah M, Idle M, Patel K, Kademani D (2018) Management update of potentially premalignant oral epithelial lesions. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2018.
21. Singh A, Thukral CL, Gupta K, Sood AS, Singla H, Singh K (2017) Role of MRI in Evaluation of Malignant Lesions of Tongue and Oral Cavity. Polish Journal of Radiology. 82:92-99.
22. Lodi G, Franchini R, Warnakulasuriya S, Varoni EM, Sardella A, Kerr AR (2016)Interventions for treating oral leukoplakia to prevent oral cancer. Cochrane Database of Systematic Reviews. 2016(7).
23. Parlatescu I, Gheorghe C, Coculescu E, Tovaru S(2014) Oral Leukoplakia – an Update. Mædica. 9:88-93.
24. Bewley AF, Farwell DG. Oral leukoplakia and oral cavity squamous cell carcinoma. Clinics in Dermatology. 35:461-467.
25. Warnakulasuriya S, Reibel J, Bouquot J, Dabelsteen E (2008) Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. Journal of Oral Pathology & Medicine. 37:127-133.
26. van der Waal I (2010) Potentially malignant disorders of the oral and oropharyngeal mucosa; present concepts of management. Oral Oncology. 46:423-5.
27. Brouns EREA, Baart JA, Bloemena E, Karagozoglu H, van der Waal I (2013) The relevance of uniform reporting in oral leukoplakia: Definition, certainty factor and staging based on experience with 275 patients. Medicina oral, patologia oral y cirugia bucal. 18:e19-e26.
28. Ishii J, Fujita K, Komori T (2003) Laser surgery as a treatment for oral leukoplakia. Oral Oncology. 39:759-769.
29. van der Waal I, Axéll T (2002) Oral leukoplakia: a proposal for uniform reporting. Oral Oncology. 38:521-526.
30. Rhodus NL, Kerr AR, Patel K (2014) Oral cancer: leukoplakia, premalignancy, and squamous cell carcinoma. Dent Clin North Am. 58:315-340.