Oral Leukoplakia

Are You Confident of the Diagnosis?

Oral leukoplakia can best be defined, in a broad sense, as any white plaque or patch that adheres to the mucosal surface and will not routinely rub off. Typically we see this finding in the grouping of “premalignant” lesions of epithelial origin. Diagnosis can often be very tricky. Time is the main characteristic that separates an oral leukoplakia diagnosis from other white lesions commonly found in the mouth. Even the best clinicians should be cautious in rendering this diagnosis based on clinical appearance alone.

Leukoplakia can often be over-diagnosed and is often confusing. The physical appearance of oral leukoplakia can often mimic many other forms of oral white lesions. The therapist and diagnostician must be able to thoroughly understand each other’s use of the term in any specific case presented to them. The final diagnosis of leukoplakia in the mouth must be accomplished via histopathologic results only so as not to confuse the practitioner with other white lesions found in the mouth

What to be alert for in the history

The practitioner must be acutely aware of the lifetime habits of the patient. A history of smoking or use of smokeless tobacco are main factors that may lead to oral carcinoma—another white lesion. The diagnosing physician should take a detailed medical assesment of the patient so as not to overlook a more significant oral disease.

These “plaques” are more frequent in older men and more often on the vermilion border of the lower lip, bucal mucosa, hard/soft palates, and less frequently on the floor of the mouth. Typically these discrete areas of mucosal thickening are multifocal or even diffuse, localized, smooth or roughened, leathery, and white.

Characteristic findings on physical examination

Leukoplakia appears as a whitish, well-defined mucosal patch or plaque caused by epidermal thickening or hyperkeratosis and cannot be scraped off (Figure 1, Figure 2, Figure 3, Figure 4). The term of leukoplakia is not applied to other white lesions such as those caused by candidiasis, lichen planus or other disorders.

Which white patches should be biopsied? Histologic examination should be made of all lesions that persist for 2 weeks after removal of local irritants. Ultimately the clincal diagnosis will be based on the pathologist’s report. The general term “leukoplakia” is merely a description of a finding. The biopsy will confirm the diagnosis, thus making the differential diagnosis of leukoplakia both very important as well as a challenge.

Diagnosis confirmation

When describing oral leukoplakia, it is important to generate a complete differential diagnosis. The following is a brief list of possible diagnoses to rule out:

LICHEN PLANUS (RETICULAR and PLAQUE-TYPE)

Reticular lichen planus appears clinically as adherent, interlacing, white striations (Wickham’s striae) that occur most frequently on the buccal mucosa or any other mucosal site. Plaque-type lichen planus appears as adherent, circumscribed, white plaques that occur most often on the dorsum of the tongue as well as any other mucosal site. Some may present as ulcerations that can be painless or painful. It is found more commonly in adult females. Malignancy rates are very low.

The use of a variety of medications may aide in controlling lichen planus. Treatment is based purely on symptomatology. Triamcinolone (Kenalog in Orabase) gel 0.025/0.1, 0.5% strength options in 15/80 g tubes, applied as a thin film on the area 2 to 3 times a day is the oral treatment of choice. Oral steroids can sometimes be used if severity worsens or patients become irritated by the lesions.

HAIRY LEUKOPLAKIA

Hyperplasia of the oral epithelium, with production of excess keratin (hyperkeratosis) caused by the Epstein-Barr virus infection, is considered an opportunistic infection. Often seen in individuals with compromised immunity secondary to HIV infection, and having a hairy surface appearance; this condition has not been related to development of oral cancer. Some lesions respond to therapy with acyclovir (Zovirax) 200mg capsules or 400/800mg tablets, 4 caps every 4 hours for 7 to 10 days.

SYPHILITIC LEUKOPLAKIA

Tertiary syphilis is typically seen on the dorsum of the tongue with an irregular outline and thickness and may also show nodular erosions. The disorder carries a high risk for malignant potential. A biopsy is the only way to confirm the diagnosis. The patient should be evaluated for cardiovascular and neurologic involvement.

DRUG/CHEMICAL BURN

Typically from a patient placing aspirin on the oral mucosa as a form of “pain relief.” Removal of the aspirin causes area to clear within 2 weeks. No further treatment is needed.

ACTINIC CHEILOSIS

A diffuse degeneration change of the lower lip from sun damage. Usually not present until at least 50 years of age, this lesion is precancerous; 10% of these cases develop into squamous cell carcinoma. Treatment involves removal of the thick nonhealing ulcers. Conventional biopsy may be necessary to confirm the diagnosis.

WHITE SPONGE NEVUS (Cannon’s Disease)

Thick bilateral white plaques with a spongy texture. The gingival margin and dorsum of the tongue are never affected. This is a benign lesion and has no treatment, as there are no serious clinical complications and it clears on its own. The condition occurs in childhood or adolescence and is inherited in an autosomal dominant manner.

VERRUCOUS LEUKOPLAKIA

Shows as a corrugated surface caused by excessive hyperkeratosis. Shown to reoccur and insidiously spreads over time, resulting in a diffuse warty-type oral lesion that may harbor a squamous cell carcinoma. This is considered a high-risk form of leukoplakia.

ERYTHROLEUKOPLAKIA (Speckled Leukoplakia)

This lesion is actually of the red-white variety but is mentioned here due to the confusion often related to the white areas around the lesion. It usually represents sites in which epithelial cells are so immature or atrophic that they can no longer produce keratin. It is often velvety and granular in nature. The circumscribed areas may or may not be elevated. The boundaries are often poor and irregular. This shows a 50% risk to progress to squamous cell carcinoma, so it is very important that the practitioner diagnose and monitor the lesion closely, and biopsy.

CARCINOMA

Invasive malignant tumor consisting of transformed epithelial cells. Surgical resection or other types of oncologic intervention are the appropriate treatments. A medical history will aid tremendously in this diagnosis, as many patients are smokers and/or alcoholics.

LEUKOEDEMA

A developmental variation caused by thickening of the epithelium as well as the accumulation of fluid within the epithelial cells. Occurs bilaterally on the buccal mucosa. No treatment needed except to monitor size of lesion. Is innocuous. More evident in dark-skinned patients.

FORDYCE’S GRANULES (Ectopic Sebaceuos Glands)

An accumulation of sebaceous glands in the submucosal connective tissue. Are multiple in number and typically yellow in color. Commonly found bilaterally on the buccal (and occasionally labial) mucosa. Painless. No treatment is necessary as lesions are innocuous.

FRICTIONAL KERATOSIS (Benign Hyperkeratosis)

A chronic area of irritation that stimulates the thickening of the epithelium due to the excess production of keratin (hyperkeratosis). Usually caused by the trauma of a broken tooth or ill-fitting denture. Painless and persistent. Treatment would be removal of the source/problem and then reevaluate in 2 weeks, with biopsy to follow if still not resolved.

Topical treatment can also be introduced if the sore is irritating to the patient; these would include benzocaine 5 or 20g tube of 20% strength (or Orabase with benzocaine) or triamcinolone (Kenalog in Orabase) with strengths of 0.025%, 0.1%, and 0.5% and in tubes of 15 and 80g. Some have reported this lesion to be associated with psychiatric illness.

ACUTE PSEUDOMEMBRANOUS CANDIDIASIS (Thrush)

An infection in the mouth caused by Candida albicans, commonly found on the epithelial surfaces. Candidiasis has an acute onset, and patients often complain of dry mouth with a bad odor. Removal of this whitish lesion will leave an erythematous mucosal surface underneath it. Because of its ability to be rubbed off, it is usually not confused with leukoplakic white lesions.

Optimal treatment is with anti-fungal medications. Clotrimazole (Mycelex) oral troches—10mg tablets in groups of 70s given 5 times a day for 14 days, or Nystatin oral suspension (100,000 units/mL in 60mL or 480mLquantities) or ointment (100,000 g/unit in 15 and 30g tubes) or pastilles (300,000 units per lozenge in doses of 30s)—are the predominant medications I recommend. Follow-up after 2 to 4 weeks is recommended.

Should fungal infection persist (or reoccur frequently), one must begin to think about the patient’s immune system being compromised and needing evaluation. Diabetes and HIV are possible underlying predisposing conditions. Fungal dissemination is a potentially serious outcome.

CHRONIC HYPERPLASTIC CANDIDIASIS

A lesion that is the same as thrush (above), but the difference being that this white lesion does NOT rub off. The lesion is painless, persistent, and noted mostly in adults. See the recommendations above for the treatment of thrush, as both are treated similiarly. A biopsy stained with periodic acid-Schiff (PAS) stain may be necessary to confirm any fungal presence. Should the lesion reoccur after 2 to 4 weeks of treatment, one must then begin to rule out systemic diseases such as HIV infection, diabetes, or other immunocompromised states.

SMOKING-RELATED LEUKOPLAKIA (idiopathic leukoplakia)

Caused by clinical exposure to chemical carcinogens generated by burning tobacco. Typically these lesions are circumscribed, adherent white plaques that vary in size and thickness. They occur most often on the lower lip, buccal mucosa, and gingiva. Special attention should be paid to those lesions on the side of the tongue, as this is the area in which malignancy tendencies are seen most often. Treatment is to counsel patients and have them cease smoking. Check the lesions at regular intervals. If they do not regress, excisional biopsy is warranted.

SMOKELESS TOBACCO (POUCH) KERATOSIS

Typically found on the labial mucosa and buccal vestibule (at the site where the smokeless irritant is placed). Is caused by chronic exposure to chemical carcinogens, similar to smoking-related leukoplakia. Treatment again requires patient counseling to cease the use of the irritant. If the patient ceases chewing and the lesion regresses on periodic examinations, then closely monitor the area. Should the area not regress or show signs of dysplastic changes, then an oral surgeon should excise the area and manage the patient based on the pathology report.

NICOTINIC STOMATITIS (pipe-smoker’s palate)

The combination of tobacco smoke and heat combustion is believed to lead to this tissue change. Predominantly on the hard palate. Besides a firm leathery appearance, these areas can have red dots within them, which are merely salivary gland ducts that have become inflamed. The risk for malignant changes are low. Elimination of the habit should reverse the palatal changes.

What is the Cause of the Disease?

Etiology

Pathophysiology

Oral mucosal lesions can appear white because of thickening of the epithelium (acanthosis), the production of excess keratin on the epithelial surface (hyperacanthosis), or accumulations of surface organisms or debris (pseudomembranes). White oral lesions have an unknown etiology and can randomly appear in any age group or at any time in a normal lifetime. Studies have shown that most oral lesions occur most often in adults over 30 years of age.

Systemic Implications and Complications

Because it is not possible to predict the biologic behavior of a leukoplakia lesion based on its clinical appearance alone, other diagnostic procedures are often necessary to determine if the lesion is premalignant or malignant. A rule of thumb that we use in dentistry is any white lesion in the mouth that does not go away in 2 weeks needs to be evaluated by an oral surgeon. In discussing this with the specialist, they will then watch the lesion for another week and determine if a biopsy is necessary.

ANY white lesion that is found that does not scrape off or is there consistantly for 2 to 3 weeks will need to be biopsied for the final diagnosis. Irritations that produce this white-type of patch demand our full attention, as these may also be a factor contributing to carcinoma. The degree of actual cellular change toward this malignancy will ultimately come from microscopic appearances of the tissue.

Treatment Options

Once the white lesion has been successfully biopsied, treatment for leukoplakia will ultimately come back to the final pathologic diagnosis of the disease. Should the diagnosis be a non-malignant form of oral leukoplakia (see Related White Lesions below) and the patient is experiencing some mild discomfort—which sometimes can happen, especially in the eldery—the recommendation is to use a topical corticosteriod cream such as clobetasol. When writing the prescription, use clobetasol 0.05% ointment and mix a dab of it with Orabase 50:50. Prescribe it as an application twice a day until the area is comfortable.

Should the evaluation demonstrate an infectious etiology, such as candidiasis, then appropriate management would include treatments such as nystatin. Other specific treatment recommendations are included for lesions described in the differential diagnoses.

Optimal Therapeutic Approach for this Disease

When discussing “how to approach” a white lesion in the category of oral leukoplakia, it is best to first comfort and reassure the patient. Patients will often overreact to lesions in the mouth, especially if they are smokers, partake in smokeless tobacco products, or use alcohol. We need to reassure the patients that only about 1% of white lesions in the mouth are malignant. The key to patient management is the initial observation of the lesion. Historically, leukoplakia is put into three broad classifications (acute, chronic, and intermediate):

ACUTE: Develops rapidly, appears for several weeks or possibly a month, is thickened in nature with ulcerations, and is most likely to become malignant

CHRONIC: Is often diffuse and thinner, resembles a white film over surface of mucous membranes, and has a duration of 10 to 20 years.

INTERMEDIATE: Is the early form of chronic leukoplakia. Typically is between acute and chronic in regard to duration and stage of development.

One must make accurate records in the patient’s chart noting the following: the size, location and composition of the lesion, any pain associated with the lesion, and how long (if at all) the patient has known the lesion to be evident. Once your initial notes are made, you have 2 weeks to wait. Have the patient return in 14 days and again you will observe the area of concern. If there are no changes, or if the lesion(s) is/are smaller in size/number, all that is necessary is to monitor the lesion(s) every 6 months at their regularly scheduled dental visits.

If you happen to notice a change in size of the lesion(s), refer the patient to an oral surgeon for either an incisional or excisional biopsy. Once those results are forwarded to you, inform the patient of your findings and proceed. If it is a non-malignant form of leukoplakia, do nothing except possibly prescribe topical treatment. Reassure the patient and monitor once every 6 months. If it is another lesion mentioned below (or otherwise) then you would follow the protocol of that diagnosis until the lesion is rectified.

Patient Management

As stated, the cause of leukoplakia is unknown. It should be noted that there is a stronger association to this progressing to oral carcinoma with the use of tobacco, especially pipe smoking and smokeless tobaccos (snuff, pouches, and chew). There is less association with ill-fitting dentures, sharp/jagged teeth, alcohol abuse, and/or irritant foods. In managing your patient, one must be sure to include in the history and physical examination all of the above contributing factors so as to be able to narrow down the differential diagnosis to be better able to manage the patient.

The finding and diagnosis of leukoplakia is an important finding, as 3% to 25% of these lesions (depending on location) will undergo transformation to squamous cell carcinoma. Keep in mind the greatest risk for said transformation is on the lip and tongue. Biopsy is warranted in most cases.

Unusual Clinical Scenarios to Consider in Patient Management

As there is a vast number of conditions that need to be considered in the differential diagnosis of leukoplakia, some special considerations might be considering a careful family history for rare syndromes (such as dyskeratosis congenita, Heck’s disease, etc). Additionally, a suspicion for immunosuppression must be maintained when lesions persist and are recurrent. An evaluation for conditions such as HIV infection would be warranted, if there is no obvious source of immunosuppresion (such as the patient being on medications such as prednisone, azathioprine, etc).

What is the Evidence?

Robinson, HBG. Colby, Kerr, and Robinson's color atlas of oral pathology. 1990.

Newland, JR, Meiller, TF, Wynn, R. Lexi-Comp's oral soft tissue diseases: A reference manual for diagnosis and management. 2008.

Kumar, Abbas, Fausto, Mitchell. Robins basic pathology. 2007.

Shafer, Hine, Levy. A textbook of oral pathology. 1982. -Philadelphia.

Regezi, Scuibba, Progrel. Atlas of oral and maxillofacial pathology. 2000..

Neville, Damm, Allen, Bouquot. Oral and maxillofacial pathology. 2002.

Cawson, Eveson. Oral pathology and diagnosis. 1987.

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