4 Management of Oral Premalignant Lesions
Oral mucosal epithelial transformation through a series of genetic and structural changes is known to occur in several mucosal diseases, with these changes ultimately producing clinical phenotypic alterations ranging from purely erythematous, smooth lesions (erythroplakia) to predominantly white patterns, or a mixed pattern of each. Lesions with altered surface qualities where papillary to verrucous features are present, proliferative verrucous leukoplakia, offers behavioral differences marked by significantly elevated risk of carcinoma development versus typical leukoplakia. Additionally, the relatively more common immune driven condition, oral lichen planus, also possesses transformation behavior in a relatively small percentage of cases. Submucous fibrosis, a common condition geographically distributed over Southeast Asia and India, forms the basis of very large numbers of oral squamous carcinoma cases within this region. Recognition of these mucosal diseases clinically and characterized by tissue biopsy can allow intervention along with long-term posttreatment follow-up.
Management of oral premalignant mucosal diseases (OPMDs) and conditions remains a clinical challenge. The goal for management of oral premalignant diseases is prevention of progression to invasive malignant disease. Possible approaches include reducing exposure to carcinogens (“environmental”) or risk of progression among exposed individuals by means of employing medical, nonsurgical means to terminate or reverse carcinogenic events. 1 The spectrum of clinically encountered oral potentially malignant epithelial disorders, often without an obvious cause, represent, over time, a range of risk of becoming malignant. Progressive accrual of genetic alterations with recognized patterns and timing have been described along a biologic pathway to malignant transformation. 2
The first step in clinical management, of course, is identifying a clinical abnormality as premalignant with a properly performed mucosal biopsy with subsequent histopathologic evaluation as the recognized standard of care. Numerous adjunctive diagnostic techniques are available to clinicians; however, most of these modalities for clinical evaluation to date lack precision, are difficult to interpret, and do not allow prediction or anticipation of clinical behavior. 3 Thus, classic pathologic analysis must be considered the most accurate and predictable diagnostic modality, although submitted tissue specimens represent a single-spot analysis at a specific time point in what represents an evolutionary biologic process that may lead to true malignant transformation, with levels and degrees of epithelial dysplasia being the morphologic hallmarks of such an evolution in most cases.
Conditions defined as potentially malignant, therefore having an increased risk of developing into squamous cell carcinoma, include leukoplakia, and a variant, proliferative verrucous leukoplakia (PVL), erythroplakia, combined leukoplakia-erythroplakia (erythtroleukoplakia or speckled leukoplakia), submucous fibrosis, oral lichen planus/oral lichenoid lesions, and possibly chronic candidiasis. The current World Health Organization (WHO) definition of leukoplakia is “a white plaque of questionable risk having excluded other (causes) known diseases or disorders that carry no increased risk for cancer,” which will serve as the benchmark for this chapter. 4 Conditions that appear clinically abnormal such as frictionally induced or traumatic keratosis, surface keratosis secondary to a chronic biting habit (morsicatio), and acute candidiasis will thus, by definition, be excluded. The global prevalence of OPMDs has been reported to range from 1 to 5%. 5 , 6 Aside from erythroplakia, the overall risk of OPMDs evolving to squamous cell carcinoma is low, with the clinical problem being that of defining or characterizing which of the individually expressed lesions will progress to dysplasia and transform to invasive cancer. The estimated rate of malignant transformation ranges from 0.13 to 36.4% at a yearly rate of 1.36%. 7 The mechanisms of transformation from a benign state to one of premalignancy and finally invasive carcinoma involve a series of genetic alterations that are cumulative, but not always reversible. These gene-based alterations may be based on hereditary susceptibility, environmental factors, or random deoxyribonucleic acid (DNA) replication errors/mutations. 8
4.3.1 Oral Premalignant Diseases
Premalignant oral mucosal disease is characterized by a biologically altered epithelium that is at risk for progression to squamous cell carcinoma that presents as several clinical phenotypes. Levels of risk for malignant transformation vary among members within this group of conditions, which include leukoplakia and its variant, PVL, erythroplakia, submucous fibrosis, and lichen planus. A more inclusive, useful but nonspecific, term, keratosis of unknown significance, includes cases that do not demonstrate reactive histologic features as well as absence of dysplasia, and thus will not be presented here. 9 Driving management considerations of OPMDs is the presence of and degree of oral epithelial dysplasia (OED), with most studies relating to leukoplakia. The spectrum of OED, regardless of which specific premalignant condition is being evaluated, is generally in keeping with the subjective grading criteria of the WHO according to which epithelial alterations range along a continuum from mild to moderate, severe, and carcinoma in situ. 10 As with pathology of the uterine cervix, useful parallels exist within this context as to the notion of intraepithelial neoplasia of the oral mucosa as well as the grading of such, although the OED grading schemes are less rigid.
The specific oral premalignant diseases discussed will include leukoplakia (idiopathic and tobacco related), the leukoplakia variant, proliferative leukoplakia, erythroplakia, submucous fibrosis, and oral lichen planus and oral lichenoid lesions. Each condition relates to variable degrees of risk in progressing to carcinoma with varying forms of management.
4.4 Management Considerations
4.4.1 Oral Leukoplakia
A broad spectrum of treatment philosophies and preferences has been published concerning the spectrum of oral mucosal conditions deemed premalignant, yet overall there is no single modality that has been studied in a carefully designed randomized clinical trial. The wide range of treatment options in the literature range from surgical to medical with widely disseminated studies analyzed in an evidence-based manner reporting limited evidence where active treatments offer no better results than placebo in reducing the risk of developing oral cancer. 11 , 12 Crucial in helping understand the entire concept of management of any oral premalignant disease is the presence or absence of epithelial dysplasia and the degree of dysplasia if present, based on biopsy analysis. The clinical relevance and importance of OED being present resides with understanding that a percentage of these lesions carry a risk of progression to invasive cancer with the risk of this progression ranging from 6 to 36%. 13 The transformation risk of oral leukoplakia ranges from 0.13 to 17.5% over a period ranging from 0.5 to 30 years. 14 , 15 What seems to be clear in most studies is the relationship between an increasingly greater risk of dysplasia transforming to invasive cancer as the degree of epithelial dysplasia increases. A reduction of risk to malignant transformation by surgical excision has been stated to be favored over active surveillance, with lesions not excised showing a significantly higher rate of transformation versus those instances where excision was accomplished. 16 Recent studies also have emphasized the role of active treatment in the form of wide local excision and/or laser ablation in substantially reducing or preventing recurrence of oral premalignant disease and cancer progression, including cases of mild epithelial dysplasia. 17 , 18
Following establishment of a diagnosis of an oral mucosal premalignant disease or condition, management, and further risk reduction, the elimination of environmental carcinogens (tobacco and alcohol consumption) may be helpful, despite an absence of proven treatment approaches to confidently prevent the development of cancer within the context of treated epithelial dysplasia. 19 Management philosophies vary widely across a spectrum of treatment modalities ranging from habit and risk factor control to medical interventions, including chemoprevention and dietary considerations, surgical removal or ablation, close surveillance and observation, and more often a combination of these strategies. It seems clear, however, that the worst possible outcome for not treating this class of conditions simply allows worsening of the disease.
For leukoplakia with proven dysplasia present, the most common treatment or interventional modality is surgical excision, with many alternative treatments published. The most predictable results are achieved within the context of lesions that are localized, discrete, and show clinically evident margins. Mehanna and colleagues noted a significant reduction in the rate of malignant transformation of dysplastic leukoplakia treated surgically versus those not having surgery, though the risk for malignant transformation was not entirely eliminated. 16
Alternative forms of surgery for treatment of oral premalignant lesions include laser ablation (CO2, most commonly), with recurrence rates ranging widely from 3 to 41% and subsequent malignant transformation rates from 0 to 15%. 20 In the cases of homogeneous leukoplakia treated with CO2 laser ablation, highest success rates were achieved with margins of 3- and 1-mm depth. 21 Unfortunately, little pooled data exist regarding predicting or documenting malignant transformation rates in higher risk leukoplakia types. Additionally, there is evidence regarding higher recurrence rates in the cases of multifocal dysplastic leukoplakia. 22
PVL was defined as a specific form of leukoplakia in 1985 by Hansen and colleagues. 23 It is separated from typical oral leukoplakia by its more aggressive biologic profile with a high recurrence rate and high risk of transformation to invasive squamous cell carcinoma. It begins as a smooth homogeneous leukoplakia plaque that advances over a wider surface area to involve multiple sites, either as a contiguous process or as a discontinuous one, assuming a multifocal distribution. Of note, affected individuals often do not carry the same risk profile as those associated with oral leukoplakia and squamous cell carcinoma. 24 Additionally, the demographic profile of PVL versus typical oral leukoplakia differs in that nonsmokers and older women dominate in published series overall, with the pathologic qualities of PVL characterized by variation within each region ranging from benign hyperkeratosis to carcinoma, with other pathologic variations including verrucous hyperplasia, verrucous carcinoma, and, less frequently, verrucous carcinoma. 25
Management options must consider the specific histopathologic features present. Often, multiple biopsies are generally performed, with an average of nine biopsies performed during the lifetime of a person with PVL. 26 The degree of dysplasia present will determine the level of management. Some treatments may relate to observation alone if dysplasia is absent, while premalignancy beyond mild dysplasia will require complete removal, by scalpel excision, laser ablation, photodynamic therapy, systemic retinoids, each with equivocal results, with surgical excision being the most commonly employed modality. 27 Some advocate the use of surgery combined with methisoprinol in the cases where papilloma virus was present in an effort to add an antiviral modality and an immunostimulant effect. 28 As recurrence and progression are very frequent, with 71% of patients recurring or progressing to carcinoma in the light of multiple treatment interventions, long-term vigilance and multiple biopsies over a lifetime are needed.
Prevention strategies, including chemoprevention, have included use of retinoids, antioxidants, cyclooxygenase-2 (COX-2) inhibitors, and vitamin A and derivatives, all without clear success in halting or reducing progression and malignant progression. Overall prognosis is poor given the recurrence rate and frequency of transformation to invasive carcinoma. 29