Looking into the whites of the mouth

By Warren R. Heymann, MD
Oct. 28, 2020
Vol. 2, No. 43

How often do you perform an oral examination? If you’re like me, probably only under two circumstances — when the patient has specific complaints (soreness, a raised lesion, or a discoloration noted by their dentist), or when we are seeking specific findings to confirm our clinical suspicions based on our cutaneous examinations (e.g., lichen planus, Darier disease, Cowden disease, etc.).

In the United States, [at least] 48,330 cases of oral and oropharyngeal cancer are diagnosed annually, comprising approximately 3% of all cancer cases. Risk factors include alcohol, tobacco, and human papillomavirus infection (notably HPV-16 and HPV-18). (1) Although head and neck mucosal melanoma is rare, accounting for only up to 4% of all melanomas, it is highly aggressive, with 5-year overall survival rates ranging from 20 to 40%. (2)

I will begin with a conclusion — we should probably routinely examine the oral cavity. I am not advocating turning dermatologists into oral surgeons (personally, other than superficial biopsies of the lip, I do not perform intraoral biopsies). Discoloration will get our attention — if dark, are we dealing with a melanoma, melanoacanthoma, amalgam tattoo, or black hairy tongue? If red, is it erythroplakia (with an up to 50% risk of malignant transformation), erythematous candidiasis, lichen planus, or lupus? (3). Most intraoral lesions, however, tend to be shades of white. Those lesions will be the focus of this commentary.

Most white oral lesions are benign. Oral leukoplakia is defined by the World Health Organization as white plaques of questionable risk, once other specific conditions and other oral potentially malignant disorders have been ruled out.

Candidiasis may be ruled out by a simple KOH examination. Lesions on the sides of the tongue in immunocompromised patients (especially HIV) may represent oral hairy leukoplakia due to Epstein Barr infection.

Frictional keratosis may be represented by linea alba, which is the white, keratotic line on the buccal mucosa approximating the occlusal [biting] plane. A biopsy is not usually necessary as these lesions will resolve upon cessation of biting. A biopsy may be considered in severe cases when they appear as eroded or ulcerated gray or white papules and plaques.

According to Müller: “Leukoedema is a common, asymptomatic buccal mucosal finding of unknown etiology and is considered to represent a normal variation. It is more common in African-Americans than in white Americans occurring in 49% of African-Americans and in 4% of white Americans in one survey of 13,000 patients. This study found no sex predilection although other studies have reported leukoedema is more commonly seen in males. Leukoedema affects the bilateral buccal and labial mucosa and appears as an opalescent, filmy gray to white lesion that characteristically diminishes upon stretching of the mucosa. This feature distinguishes leukoedema from frictional keratosis, lichen planus and leukoplakia. Although leukoedema is generally not biopsied, histologic findings of parakeratosis and spongiosis is seen.” (4)

Heck’s disease (focal or multifocal epithelial hyperplasia) is a benign, rare condition of the skin and mucous membranes induced by human papillomavirus (HPV-13) infection. Heck’s disease occurs at increased rates among Eskimos, Native Americans, and Latino Americans; the disorder is mostly seen in children and females. Immunocompromised patients are at increased risk. There are two clinical types of Heck’s disease:

1. papulonodular subtype: noted mostly in young patients, this affects the buccal and labial mucosa, palate, and oral cavity commissures, appearing pink and smooth;

2. papillomatous subtype: noted mostly in adults, occurring on the lingual and gingival tissues, appearing white with cobblestoning.

The disease course is one of spontaneous remission and recurrences. HPV immunotyping may differentiate Heck’s disease from condyloma due to HPV-6 or HPV-11. (5)

White sponge nevus (WSN) is a rare benign inherited disorder of autosomal‐dominant transmission that involves mutations in the cytokeratin 4 and cytokeratin 13 genes. These mutations cause keratin instability and tonofilament aggregation, resulting in whitish lesions on nonkeratinized epithelial surfaces. Familial cases are infrequent due to irregular penetrance of the trait. WSN clinically appear as asymptomatic white or gray diffuse, thickened, corrugated or velvety painless plaques predominantly on the bilateral buccal mucosa, followed by lips, alveolar ridges, and the floor of the mouth. Other potentially affected sites include nasal, esophageal, rectal, or vaginal mucosae. WSN usually develop during early childhood with no racial or gender predilection, presenting varied sizes and distribution, and may change over time. WSN is a painless benign condition requiring no treatment. (6) I am aware of only a solitary case of a squamous cell carcinoma developing within a WSN in a 59-year-old asthmatic woman on prednisone. (7) Similar to WSN, hereditary benign intraepithelial dyskeratosis (HBID) is a rare autosomal dominant disorder initially described in the tri-racial Native American tribe in North Carolina. Similar to WSN, HBID presents as white spongy plaques on the buccal mucosa and tongue, but also displays ocular findings of white gelatinous conjunctival plaques. (4). According to OMIM, HBID has been mapped to the telomeric region of 4q35, although precise mutations have not been defined.

Now that we have ruled out myriad oral white lesions, we are back to leukoplakia itself, which refers to any white plaque occurring in the oral cavity. Lesions are considered homogenous or nonhomogeneous (with 3 variants — speckled, nodular, or verrucous). Leukoplakia prevalence is approximately 2%, usually noted in the fifth to sixth decade of life. The overall malignant transformation rate ranges from 1.5 to 34%. Proliferative verrucous leukoplakia (PVL) requires special attention as the reported malignant transformation may approach 100%. PVL is usually seen in women > 60 years old, with the gingivae being the most commonly affected site. (4)

I am writing this commentary on the cusp of New Year’s Eve 2020. Perhaps a good resolution for the new year would be to open my mouth less, and my patients’ mouths more.

Point to Remember: Dermatologists should consider performing oral examinations with an appreciation for benign lesions and those that have malignant potential.

Our Experts’ Viewpoints

Drore Eisen MD, DDS
Dermatologists of Southwest Ohio
Cincinnati, OH

As Dr Heymann eloquently points out, when establishing a diagnosis of leukoplakia, it is important to differentiate oral white lesions that do not have a cause (idiopathic leukoplakia) from white lesions which do, such as: benign frictional keratosis (i.e. from a sharp or broken tooth), candidiasis, lichen planus, congenital lesions (white sponge nevus, dyskeratosis congenita, pachyonychia congenita), frank carcinoma, and others. Leukoplakia is the most common precursor of oral cancer with malignant transformation developing in up to 34% of lesions over time. Early identification and treatment of these oral precancerous lesions can have a dramatic impact on the dismal oral cancer mortality rates. In 2019, over 10,000 individuals died from oropharyngeal cancer vs. approximately 7,200 from melanoma. Unlike visual inspection of pigmented skin lesions, which is a reliable screening method for detecting melanoma, visually differentiating oral precancers and even oral cancers from benign lesions is difficult, even by highly trained experts. Leukoplakia with histologic changes of dysplasia, present in up to 25% of biopsy samples, and early cancers often have no distinctive clinical features and can appear identical to totally benign lesions. Therefore, biopsy with histologic evaluation of these lesions is imperative to rule out dysplasia. Mixed white and red lesions (erythroleukoplakias or speckled leukoplakias), and those that develop on the floor of the mouth or on the ventrum of the tongue and the lip should be viewed with even greater suspicion as these are more likely to exhibit dysplasia on biopsy. The most effective method of combating oral cancer is by early detection, diagnosis, and eradication of early lesions and their precursors. Since the oral cavity is the only region of the aerodigestive tract that can be effectively screened, dermatologists should be encouraged to perform oral cancer examinations, especially in those who abuse tobacco and/or alcohol, well established independent risk factors for oral cancer development, accounting for approximately three-fourths of all oral and pharyngeal cancers in the United States.

1. Li CC, Shen Z, Bavarian R, Yang F, Bhattacharya A. Oral cancer: Genetics and the role of precision medicine. Surg Oncol Clin N Amer 2020; 29: 127-144.

2. Moya-Plana A, Mangin D, Dercle L, Taouachi R, et al. Risk-based stratification in head and neck mucosal melanoma. Oral Oncol 2019; 97: 44-49.

3. Wetzel SL, Wollenberg J. Oral potentially malignant disorders. Dent Clin N Amer; 2020; 64: 25-37.

4. Müller S. Frictional keratosis contact keratosis and smokeless tobacco keratosis: Features of reactive white lesions of the oral mucosa. Head Neck Pathol 2019; 13: 16-24.

5. Schwartz Z, Magro C, Nuovo G. The molecular-based differentiation of Heck’s disease from its mimics including oral condyloma and white sponge nevus. Ann Diagn Pathol 2019; 43: 151402.

6. Bezerra KT, Leite TC, Roza ALOC, Araújo R, et al. White sponge nevus: A condition not always clinically suspected. J Cutan Pathol 2020; 47: 22-26.

7. Downham TF II, Plezia RA. Oral squamous cell carcinoma within a white sponge nevus. J Dermatol Surg Oncol 1978; 4: 470-472.

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