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Premalignant Lesions of the Oral Mucosa
Introduction
The premalignant oral disorder is a blanket term for a variety of pathologies that can arise in the oral cavity. Early recognition and prompt management are key to optimal outcomes. However, there remains a significant knowledge gap in this area among medical practitioners.[1] A recent systematic review revealed that less than half of medical practitioners were aware of common risk factors of premalignant oral lesions or oral carcinoma; further, a low level of awareness was noted among most medical practitioners of common premalignant oral cavity lesions. Thus, there remains a significant need to understand and recognize the presentation, pathophysiology, and management of these conditions.
The oral cavity is an anatomical site defined by an area that includes the lips, gums, buccal mucosa, gingiva/alveolar ridge, hard palate, the floor of the mouth, and oral tongue (anterior 2/3). The vestibule is comprised of the buccal and labial aspects of dentition, as well as the mucosa of the alveolus and wet border of the lip.[2] Stratified squamous epithelium lines the majority of the oral cavity, and aberrancy in this epithelium is often what gives rise to premalignant oral lesions.
The most commonly described premalignant oral lesions are leukoplakia, erythroplakia, lichen planus, and submucous fibrosis.[3][4][5][6] This review will describe the etiology, pathophysiology, pertinent history, and exam findings, as well as management options for these oral cavity malignant precursors.
Etiology
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Etiology
The most commonly described etiologies of premalignant oral lesions are cigarette smoking, tobacco, and alcohol exposure.[7][8] Betel nut chewing has also been associated with the development of oral leukoplakia.[9] Human papillomavirus (HPV) has emerged as a risk factor: a recent meta-analysis of 52 studies revealed a pooled HPV DNA prevalence of 22.5% in oral premalignant disorders.[10] The authors also noted that HPV16 was the predominant genotype, which is also the most common serotype found in oropharyngeal cancer.[11]
Epidemiology
Oral premalignant lesions occur in roughly between 1.5% and 4.5% of the world's population and disproportionately affect men compared to women.[12][13] The highest rates were found in Asian, South American, and Caribbean populations, as geographical variance exists due to differing rates of tobacco and alcohol consumption. Oral premalignant lesions account for 17% to 35% of all new cases of oral cavity cancer and undergo malignant transformation between 0.7% and 2.9% annually.[14][15]
Pathophysiology
The oral cavity is lined with stratified squamous epithelium, which is exquisitely sensitive to carcinogenic insult. Exposure to tobacco, alcohol, betel nut, or human papillomavirus can result in a cellular microenvironment that results in the formation of dysplastic or hyperkeratotic epithelium. This manifests clinically as oral leukoplakia, erythroplakia, or lichen planus. These entities have varying rates of progression to carcinoma, though dysplastic epithelium can be present in any of these pathologies, highlighting the need for histopathological evaluation.[16] The pre-malignant nature of oral lichen planus remains controversial versus oral lichenoid lesions showing more established pre-malignant potential.[17]
Oral submucous fibrosis is a separate entity that is caused specifically by betel nut use. Chronic betel quid use results in submucosal fibrosis, leading to progressive oral cavity scarring leading to trismus, dysphagia, or odynophagia. Oral submucous fibrosis may present in isolation but can also be found concurrently with leukoplakia or erythroplakia.[18]
Histopathology
Histopathology of oral leukoplakia often reveals hyperkeratosis or parakeratosis with varying degrees of inflammation. Hyperplastic epithelium may be present, in addition to mild, moderate, or severe dysplasia. Carcinoma in situ or frank carcinoma also may be present.[19]
Erythroplakia often has similar features on histological evaluation, including varying degrees of dysplasia; erythroplakia lesions harbor carcinoma more frequently than leukoplakic lesions.[20] Lichen planus can similarly display hyperkeratosis, in addition to lymphocytic infiltration and Civatte bodies.[21] Finally, oral submucous fibrosis exhibits characteristic collagen hyalinization and deposition of fibrotic material in the submucosa and muscularis.[18]
History and Physical
Evaluation of oral lesions requires thoughtful evaluation and close attention to physical exam findings. In assessing a patient with a possible premalignant oral lesion, the clinician must elicit the length of time the lesion has been present, the evolution of the lesion (change in character or size), presence or absence of pain or recent dental trauma, bleeding, associated dysphagia, odynophagia, trismus, or weight loss, as well as the history of smoking or alcohol exposure. Special attention to medical history, including autoimmune disorders or history of solid organ transplant, is vital, as these patients are at higher risk of developing oral cavity carcinoma.[22][23]
Certain viral illnesses can predispose patients to premalignant oral lesions, including human immunodeficiency virus or Hepatitis C. Hepatitis C is often comorbid with oral lichen planus.[24] On physical exam, it is important to characterize size, shape, description, color, firmness, and location of the lesion, along with the presence of cervical or parotid lymphadenopathy if it is present. Leukoplakia will present as a white patch or plaque in the oral cavity, which cannot be wiped off, whereas erythroplakia may present as a firm red patch or plaque; both are usually non-tender lesions. The lesion can be diffuse or well-circumscribed and may involve the wet border of the lip, floor of the mouth, oral tongue, or buccal mucosa.
On the other hand, oral submucous fibrosis usually involves the oral tongue and may include portions of the oropharynx. There is often a pale discoloration of the mucosa with a mottled appearance and may result in trismus in advanced cases. Finally, oral lichen planus may present as an ulcerative, tender lesion with a fine reticular appearance, often of the oral tongue or buccal mucosa.[22]
Figures 1-3 display a variety of leukoplakic lesions of the oral cavity.
Evaluation
Evaluation of premalignant oral lesions consists of both physical exam and biopsy. As noted above, a careful bimanual exam with appropriate illumination is paramount. Tissue sampling is warranted to rule out frank malignancy in most cases. If the lesion is diffuse or involving multiple subsites, several samples from different sites should be obtained. If moderate or severe dysplasia is present on histopathology, excisional biopsy with appropriate margins should be strongly considered to formally exclude malignancy.[25]
Contrasted computed tomography from the skull base to the clavicle is recommended if malignancy is suspected or if cervical adenopathy is present. Imaging allows for further characterization of the lesion as well as in staging in the case of malignancy.
Treatment / Management
Management of premalignant oral lesions is focused mainly on the prevention of oral cavity carcinoma. Based upon the histopathology of the lesion and patient preference, cessation of risk factors including alcohol, tobacco, and betel nut, along with close observation, are a reasonable option in patients with low-risk lesions. However, in patients with high-risk lesions (with moderate or severe dysplasia on histopathology or high-risk sites such as the lateral border of tongue or floor of mouth), excisional biopsy is the management of choice. Several methods are available, including laser ablation or formal excision.
The obvious limitation of laser ablation is that formal histopathological evaluation of the entire lesion is not feasible due to the destructive nature of laser ablation. A recent study found that when compared to simple biopsies, whole lesion excision revealed a 7% rate of occult carcinoma and a 79% variation in the degree of dysplasia present in the initial biopsy.[26] (B2)
Therefore, excisional biopsy is the gold standard of treatment if clinical suspicion remains. The only randomized trial evaluating surgical excision vs. smoking cessation and close observation in a total of 260 patients with nondysplastic oral leukoplakia revealed a nonsignificant difference in the development of carcinoma between the two arms, suggesting that watchful waiting may be feasible in otherwise low-risk patients.[27] (A1)
Several nonsurgical treatments, including non-steroidal inflammatory drugs and retinoids, may be effective, yet high-level data supporting these treatments is lacking.[28] Lichen planus, in particular, may be managed with topical corticosteroids with varying degrees of success.[24](A1)
Differential Diagnosis
Several other entities may mimic oral premalignant lesions, including squamous cell carcinoma, oral candidiasis, oral hairy leukoplakia, oral mucositis or graft versus host disease, autoimmune lesions (i.e., discoid lupus), or Kawasaki disease. Histological evaluation remains the gold standard for differentiating these pathologies.
Prognosis
Prognosis of oral premalignant disorders centers mainly upon the clinical presentation of the lesion and the degree of dysplasia present on histopathology. Close follow-up is recommended in these patients, especially in those with risk factors such as tobacco use, immunosuppression, or severe dysplasia, as a recent study showed that up to half of treated patients develop recurrence or new lesions and up to a fifth can develop invasive carcinoma.[29] In some practices, quarterly follow-up is performed in high-risk patients, and at least biannual follow-up is recommended in low-risk patients.
Complications
The most feared complication of oral premalignant disorders is progression to carcinoma. A recent meta-analysis revealed that the rate of malignant transformation of all oral premalignant disorders combined was around 7.9%. In contrast, lichen planus alone is around 1.4%, leukoplakia 9.5%, oral submucous fibrosis 5.2%, and erythroplakia 33.1%.[30] Close follow-up and possible surgical intervention are thus essential for the prevention and early detection of oral carcinoma.
Deterrence and Patient Education
Patient education and deterrence of tobacco, alcohol, and betel nut exposure are essential to preventing further epithelial toxicity and oral premalignant disorders.
Pearls and Other Issues
To avoid the development of oral cavity carcinoma, histological evaluation is essential. Surgical excision is recommended for high-risk lesions. Low-risk lesions managed with observation must be closely followed and physical exam findings documented appropriately to assess interval changes.[25] Photo documentation can aid in this endeavor as well.
Enhancing Healthcare Team Outcomes
Due to the risk of malignant transformation of oral premalignant disorders, prompt diagnosis is critical. Management of oral premalignant disorders is complex and requires an interprofessional team approach, including the expertise of pathologists, surgical oncologists, and radiologists, in addition to the auxiliary staff. Nurses and pharmacists may also play a role in some cases. In patients treated non surgically, pharmacists play a vital role in managing medications and ensuring no adverse effects occur. An interprofessional team-based approach is paramount to patient outcomes and the prevention of oral cavity carcinoma. [Levle 5]
Media
(Click Image to Enlarge)
Leukoplakia of the ventral tongue and floor of mouth
Contributed by David Hernandez, MD
(Click Image to Enlarge)
Leukoplakia of the lateral border of the tongue
Contributed by David Hernandez, MD
(Click Image to Enlarge)
Leukoplakia of the gingiva
Contributed by David Hernandez, MD
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