Smokeless Tobacco Oral Pathology

Etiology

Smokeless tobacco keratosis is caused by constant frictional irritation of smokeless tobacco against the oral mucosa (see Image. Buccal Vestibule with Hyperkeratosis).[4] The formation rate depends on the frequency of habit, dose, and even the brand used. Leukoplakia has multiple etiologic agents, including tobacco, alcohol, betel nut/sanguinaria, ultraviolet radiation, microorganisms, and/or trauma (see Image. Leukoplakia on the Mouth Floor).[5] Erythroplakia is strongly associated with tobacco and alcohol consumption, with some correlations associated with betel quid chewing (see Image. Erythrolakia, Posterior Aspect of the Mouth).[6][7] 

Verrucous carcinoma is a low-grade variant of squamous cell carcinoma (see Image. Buccal Vestibule With Hyperkeratosis and Verrucous Carcinoma). While its etiology is not clearly defined, human papillomavirus, smoking, poor oral hygiene, lichenoid lesions, or chewing tobacco have been attributed to its causation.[8] Squamous cell carcinoma has a variety of etiologies, with smoking and alcohol consumption regarded as significant risk factors. This is due to their synergistic effect in the development of malignancy and their associated usage in 90% of all reported cases.[9][10]

Epidemiology

Smokeless tobacco keratosis presents in 15% of chewing tobacco users and 60% of snuff users. Results from an epidemiological study by Rimal et al showed that smokeless tobacco keratosis was the most prevalent premalignant disorder found in 50.4% of their analyzed population.[11] Leukoplakia typically presents in patients older than 40, with an average age of presentation at 60. Leukoplakia is an uncommon disease process in young patients.[12] Approximately 70% of these lesions are found on the vermilion border, buccal mucosa, or the gingiva. 

Erythroplakia presents in roughly 0.02% to 0.83% of patients and is commonly seen in middle-aged and older adults.[6] Verrucous carcinoma presents an incidence of approximately 6% of all oral carcinomas.[13] These lesions have a predilection in men and typically present at a median age of 62 years.[14] Oral cancer is 2 to 3 times more prevalent in men compared to women in most ethnic groups.[10] Cancers of the head and neck represent nearly 700,000 of all diagnosed malignancies per year.[15] Of the annually diagnosed oral carcinomas, squamous cell carcinoma accounts for approximately 90% of rendered diagnoses.

Pathophysiology

Smokeless tobacco keratosis results from chronic irritation from the placement of smokeless tobacco, usually in the buccal vestibule. This irritation results in the deposition of excess fibrin-like material throughout the submucosa and an increase in keratin production, which results in the characteristic white corrugated appearance of the epithelium (eg, the mucosa) (see Image. Tongue, Lateral Border With Ulcerated Lesions). Leukoplakia and erythroplakia are clinically diagnostic terms. These lesions can result from multiple pathophysiological processes that result in their appearance.[16]

Verrucous carcinoma, a low-grade presentation of squamous cell carcinoma, has an increased keratin production, giving it a verrucous, wart-like appearance. In addition, the epithelium thickens (hyperplasia); however, very little dysplasia is seen within the epithelium. Squamous cell carcinoma develops due to dysplastic changes throughout the epithelium, disrupting the basement membrane and invasion into the connective tissue; these changes cause abnormal growth or atrophy of epithelial tissue.

Histopathology

Smokeless tobacco keratosis may present with a nonspecific appearance, with hyperkeratotic and/or acanthotic squamous epithelium. Intracellular edema and increased subepithelial vascularity may also be noted. Parakeratin chevrons above or within the superficial epithelial layers can generally be visualized. Therefore, histologic examination of these lesions should evaluate for epithelial dysplasia. 

Leukoplakia presents with hyperkeratosis, a thickened keratin layer, possible acanthosis, and a thickened spinous layer. Notably, diagnosing leukoplakia is a clinical term only, and a biopsy is required to determine a definitive diagnosis. The biopsy should be collected from the most severe site. Over 90% of erythroplakia lesions present histopathologically with epithelial dysplasia, carcinoma in situ, or superficially invasive squamous cell carcinoma. Keratin is typically not produced, and epithelium atrophy is generally noted. 

Verrucous carcinomas have a deceptively benign histopathologic presentation. These lesions exhibit wide, elongated rete pegs that push into underlying connective tissue and have abundant parakeratin clefts between surface projections. The epithelial cells are not generally dysplastic; however, an intense inflammatory infiltrate will likely be noted in the submucosa.[17] Squamous cell carcinoma arises from the dysplastic epithelium. Histologically, it presents as cords or islands of malignant epithelial cells penetrating/invading through the basement membrane into the submucosa below. In addition, severe inflammatory cell infiltrates within the submucosa are often noted in response to the invasion.

History and Physical

Smokeless tobacco keratosis presents as a characteristic white corrugated plaque on the oral mucosa where the tobacco is placed. Early lesions present as a white film that, over time, becomes more keratotic with distinct pouching.[4] Leukoplakia is a white patch or plaque that cannot be characterized clinically or pathologically as any other disease. These lesions get their color from the thickened keratin or spinous layer.

Erythroplakia is a red patch or plaque that cannot be clinically diagnosed as any other condition. Commonly, these lesions are well-demarcated, erythematous, asymptomatic patches with a velvety texture. At times, lesions may display a combination of erythroplakia and leukoplakia, which are then termed erytholeukoplakia. While less common than leukoplakia, erythroplakia and erytholeukoplakia have a higher malignant potential, with most biopsied cases exhibiting dysplasia or carcinoma in situ.[18][19] Common sites are the floor of the mouth, tongue, and soft palate.

Verrucous carcinoma presents as a diffuse, well-demarcated, painless plaque with papillary or verruciform projections. These lesions are typically white but can appear pink depending on the amount of keratin production and the increase in the underlying vasculature. Verrucous carcinomas typically present on the mandibular vestibule, buccal mucosa, gingiva, tongue, and hard palate. When associated with smokeless tobacco use, it typically corresponds to the location of chronic tobacco placement. Squamous cell carcinoma can have a variety of presentations. Generally, the hallmark presentation is deep ulceration with rolled borders in a high-risk area, such as the tongue's posterior-lateral aspect or the mouth's floor.

Evaluation

Smokeless tobacco keratosis can be diagnosed through clinical examination and patient interviews. If a corrugated buccal mucosa is noted, the patient should be questioned regarding the use of smokeless tobacco. In addition, the clinician should determine if the location where the patient places the tobacco correlates with the lesion identified. Leukoplakia should be evaluated closely, as more than 33% of oral carcinomas exhibit leukoplakia before becoming a true malignancy. As a clinical diagnostic term, an effort to identify any clinical source or cause of the lesion should be explored.[20]

Erythroplakia may present similarly to other lesions, ranging from benign to malignant. The red color is due to atrophy of the epithelium, which exposes the microvasculature of the underlying tissue. These lesions should be biopsied after ruling out all clinically possible causes to determine whether epithelial dysplasia or malignancy is present.

Verrucous carcinoma should be evaluated closely, as it is a low-grade variant of squamous cell carcinoma and may be easily overlooked and/or misdiagnosed.[21] With varied clinical presentations, squamous cell carcinoma should be evaluated closely. In addition, patients must be interviewed in-depth about their habits to determine if they are at high risk for developing oral cancer.[22]

Treatment / Management

Smokeless tobacco keratosis will typically self-resolve with cessation of the habit. Patients may be counseled initially on switching the location of tobacco placement and then followed up for evaluation of the area 2 weeks later. In this time frame, early to moderately developed lesions should self-resolve, with more advanced lesions either requiring more time to resolve or should be considered potentially malignant. The clinician should counsel the patient on smoking cessation, as switching sides could introduce a risk of dysplastic changes in other sites within the mouth.

Leukoplakia should be treated as a precancerous or premalignant lesion, as the frequency of transformation into a malignancy is greater than that of normal, unaltered mucosa. Treatment of erythroplakia is guided by histopathological diagnosis. If any evidence of dysplasia is noted, complete surgical excision and close clinical follow-up are warranted, as recurrence and multifocal involvement are common.[7] One in 5 verrucous carcinomas will develop into squamous cell carcinoma, so early treatment is paramount.(B2)

The treatment of choice for these lesions is surgical excision with clear margins (normal tissue) to reduce the chance of recurrence. Squamous cell carcinoma should be excised entirely to achieve clear margins and reduce the potential for recurrence. In addition, patients should be counseled on their high-risk behaviors to aid in reducing their risk of recurrence or the development of a new primary lesion.

Differential Diagnosis

The differential diagnosis includes the following:

Smokeless Tobacco Keratosis

• Frictional keratosis
• Leukoplakia
• Squamous cell carcinoma

Leukoplakia

• Leukoedema
• Linea alba
• Morsicatio buccarum/linguarum
• Squamous cell carcinoma 

Erythroplakia

• Mucositis
• Candidiasis
• Psoriasis
• Vascular lesions
• Squamous cell carcinoma

Verrucous Carcinoma

• Proliferative verrucous leukoplakia
• Verruca vulgaris
• Squamous papilloma

Squamous Cell Carcinoma

• Erythroleukoplakia
• Traumatic ulcerative granuloma with stromal eosinophilia 
• Oral manifestation of deep fungal infection

Prognosis

Smokeless tobacco keratosis has a guarded but good prognosis; however, the resolution is highly patient-dependent. More advanced lesions may require biopsy and further monitoring for potential malignant changes. Leukoplakia has a guarded prognosis, as the term is a strictly clinical diagnosis. Since premalignancy has potential, these lesions should be considered precancerous until an otherwise benign diagnosis is rendered.[23] Erythroplakic lesions have a guarded prognosis, as most present with some form of epithelial dysplasia.[24]

Verrucous carcinoma, like a low-grade variant of squamous cell carcinoma, has a guarded prognosis. Surgical excision typically eliminates the lesion itself; however, there is a high potential for recurrence without cessation of high-risk behaviors. Squamous cell carcinoma has a poor prognosis despite therapeutic advances in treatment.[10] The key to increasing this condition's survivability is identifying and eliminating risk factors, early diagnosis, and treatment. Oral cancers have a 5-year survival rate of approximately 50%.[23]

Complications

Smokeless tobacco keratosis is the direct result of a habit. Consequently, if a patient is not willing to cease or even reduce their use of smokeless tobacco, the lesion will not resolve. Therefore, patients should be appropriately counseled. Leukoplakia and erythroplakia are clinical diagnoses and require biopsy for a definitive diagnosis. Verrucous and squamous cell carcinoma are malignant processes that should be treated promptly to improve the patient’s quality of life. Depending on the staging, patients may undergo extensive surgical interventions followed by chemotherapy and/or radiation, which will significantly impact their quality of life.