Facts on Leukoplakia (Etiology, Clinical Features, Histopathologic Features, Treatment and Prognosis)

Leukoplakia
(leuko-white; plakia-patch)

• Oral leukoplakia is defined by the WHO as “a white patch or plaque that cannot be characterized clinically or pathologically as any other disease”.
• Thus a diagnosis by exclusion.
• The term is strictly a CLINICAL one and does not imply a specific histopathologic tissue alteration.
• Leukoplakia is the most common oral precancer.

Leukoplakia:  A Premalignant or Precancerous Lesion

• Although leukoplakia is not associated with a specific histopathologic diagnosis, it is considered to be a premalignant lesion for the risk of malignant transformation is greater in a leukoplakic lesion than that associated with normal or unaltered mucosa.
• Despite the fact that leukoplakia is a premalignant lesion it should be noted that not every lesion shows histopathologic evidence of epithelial dysplasia or frank malignancy (squamous cell carcinoma).
• In fact, dysplastic epithelium or invasive carcinoma is found in only 5 to 25 % of the biopsy samples of leukoplakia.

Leukoplakia:  Malignant Transformation Potential

• Overall, the malignant transformation potential of leukoplakia is 4 % (estimated lifetime risk).
• However, specific clinical subtypes are associated with much high potential malignant transformation rates (as high as 47 %).

  Leukoplakia:  How Common Is It?

• Leukoplakia is by far the most common oral precancer, accounting for 85 % of such lesions.  (Note: this statement is not saying that leukoplakia has the highest malignant transformation risk of the premalignant group of lesions for erythroplakia [erythroplasia] does).
• Leukoplakia is also a relatively common lesion for it is estimated that approximately 3 % of all white adults will be affected at some time.  Additionally, Bouquot in his study of oral mucosal lesions found it to be the most common of all.

Leukoplakia:  Etiology

• The cause of leukoplakia remains unknown.
• Over the years the following have been considered:  tobacco, alcohol, sanguinaria, ultraviolet radiation, microorganisms and trauma.

Changes in Epithelium

Etiology of Leukoplakia:  The Role of Tobacco

• The habit of tobacco smoking appears most closely associated with leukoplakia development.
• 80 % of patients with leukoplakia are smokers.
• Smokers are much more likely to have leukoplakia than non-smokers.
• Heavier smokers have greater numbers of and larger lesions than light smokers.
• A large proportion of leukoplakias in persons who stop smoking either disappear or become smaller soon after discontinuing the habit.

Etiology of Leukoplakia:  The Role of Alcohol and Sanguinaria

• Alcohol, which seems to have a strong synergistic effect with tobacco in oral cancer development, has not been associated with leukoplakia.
• Sanguinaria (blood root) is a herbal extract that has been used in toothpaste and mouthwash.
• Over 80 % of the patients with vestibular/maxillary alveolar leukoplakias have a history of using a sanguinaria containing product as compared to 3 % of the “normal” population; some lesions have persisted after the patient stopped using the product.

Etiology of Leukoplakia:  The Role of Ultraviolet Radiation

• Ultraviolet radiation has been associated with leukoplakia of the vermilion of the lower lip.
• This leukoplakia is usually associated with actinic cheilosis.

Etiology of Leukoplakia:  The Role of Microorganisms

• Treponema pallidum has been implicated in leukoplakia of the dorsal surface of the tongue in patients with syphilis.
• Candida albicans has been demonstrated histologically in the hyperplastic/dysplastic epithelium of lesions termed candidal leukoplakia and candidal hyperplasia.
• Human papillomavirus (HPV), particularly subtypes 16 and 18, have been identified in some oral leukoplakias.
• However, HPV has also been demonstrated in normal oral epithelial cells.

Etiology of Leukoplakia:  The Role of Trauma

• Several keratotic lesions, which until recently have been viewed as variants of leukoplakia, are now considered not to be premalignant.
• Included in this group are lesions termed nicotine stomatitis and frictional keratosis.
• These keratoses are readily reversible after the elimination of the trauma or chronic irritation.

Leukoplakia:  Clinical Features

• Leukoplakia usually affects people over the age of 40 years (average age is 60 years).
• Prevalence increases rapidly with age particularly in males.
• Approximately 8 % of the males over the age of 70 years are reportedly affected.
• Approximately 70 % of the oral leukoplakias are found on the lip vermilion, buccal mucosa and gingiva.
• Note: Lesions of the tongue, lip vermilion and floor of the mouth account for more than 90 % of those that show dysplasia or carcinoma upon histologic examination.
• Individual lesions vary in clinical appearance and tend to change over time.
• Early/mild lesions usually appear as slightly elevated gray or gray-white plaques, which may appear translucent, fissured or wrinkled and are typically soft and flat.
• Early/mild lesions are usually well demarcated but may blend into the surrounding normal mucosa.
• Early/mild thin leukoplakia, which seldom shows dysplasia on biopsy, may disappear or continue unchanged.
• If the cause (s) of the lesion are not removed, many lesions will gradually become thicker and larger.
• The clinical appearance (s) of leukoplakia and the anticipated underlying histopathologic changes are presented in the following diagram.

Proliferative Verrucous Leukoplakia (PVL)

• PVL is a special high risk form of leukoplakia.
• It is characterized by multiple keratotic plaques with rough surface projections although initially beginning as a simple flat hyperkeratosis.
• PVL plaques tend to spread slowly, yet progressively.
• PVL usually transforms into a squamous cell carcinoma within about 8 years.
• PVL has a strong female predilection (1:4 male to female) and minimal association with tobacco usage.

Leukoplakia:  Histopathologic Features

• Leukoplakia is characterized by a thickened keratin layer (hyperkeratosis) with or without a thickened spinous layer (acanthosis).
• Some leukoplakias show surface hyperkeratosis but with atrophy or thinning of the underlying epithelium.
• Variable numbers of chronic inflammatory cells are typically noted within the underlying connective tissue.
• While most leukoplakias show no dysplasia on biopsy, some 5 to 25 % of the cases do show evidence of epithelial dysplasia (or squamous cell carcinoma).
• The histopathologic alterations of dysplastic epithelial cells are outlined in the next slide.

hyperkeratotosis

Moderate dysplasia

Carcinoma In-situ

Histopathologic Alterations of Dysplastic Epithelial Cells

• Enlarged nuclei and cells.
• Large and prominent nucleoli.
• Increased nuclear-cytoplasmic ratio.
• Hyperchromatic (dark-staining) nuclei.
• Pleomorphic (abnormally shaped) nuclei and cells.
• Dyskeratosis (premature keratinization)
• Increased mitotic activity and abnormal mitotic figures

Leukoplakia:  Treatment and Prognosis

• Leukoplakia represents a clinical diagnosis and therefore the first step in treatment is to arrive at a definitive diagnosis via biopsy and histologic examination of the tissue.
• Treatment depends upon the diagnosis and any leukoplakia exhibiting moderate epithelial dysplasia or worse warrants complete removal if possible.  Treatment of lesions exhibiting less severe changes is guided by the size of the lesion and its response to more conservative measures such as eliminating tobacco use.
• Leukoplakia not exhibiting dysplasia often is not excised but clinical evaluation every 6 months is recommended.
• Additional biopsies are recommended if smoking continues or if clinical changes increase in severity.
• The following diagram represents the various clinical appearance of oral leukoplakia and the anticipated underlying associated histopathologic changes.
• Complete removal of oral leukoplakia can be accomplished with equal effectiveness by surgical excision, electrocautery, cryosurgery or laser ablation.
• Long-term follow-up after removal is mandatory because of recurrence potential and because new leukoplakias may occur.
• Malignant transformation potential is related to clinical appearance and the degree of dysplasia present.