Histologic Findings
The histopathologic features are highly variable, ranging from hyperkeratosis and hyperplasia to atrophy and severe dysplasia. The histologic assessment of oral epithelial dysplasia is notoriously unreliable. Many studies show interpathologist and intrapathologist variation in diagnosing dysplasia. Clearly, molecular studies are indicated to introduce more objectivity. Studies of p53 and other molecular markers, loss of heterozygosity (LOH), and DNA ploidy as molecular markers are currently underway. [25] LOH on bands 3p and/or 9p, survivin expression, expression of matrix metalloproteinase (MMP)–9, and DNA content are potential markers for increased risk of progression from oral dysplasia to cancer. [26]
Aneuploidy is associated with increased risk of progression to squamous carcinoma. [20] Microarray analysis using reverse-transcriptase polymerase chain reaction shows candidate biomarkers in cases resulting in cancer formation. [27] On the cellular level, Wagh et al studied 420 oral leukoplakia cases and found that the average numbers of micronuclei were 1.14 in the control group, 2.63 in the potentially malignant group, and 4.88 in the confirmed malignancy group. [28]
Besides the fact that the criteria for diagnosing dysplasia are ill defined, another serious problem exists. A tissue specimen from a biopsy may not be representative of the whole lesion. Latent or unsampled dysplasias or carcinomas may be missed. [29]
Molecular Findings
The driver of malignant change within oral mucosal tissues is related to complex genetic and epigenetic changes, as noted in many cancers. Chromosomal instability, including altered telomerase function, loss of heterozygosity, and levels of DNA aneuploidy, have been reported and can predict the progression of premalignant oral lesions. Of note, both aneuploid as well as diploid lesions may progress to malignancy, with large variability noted in such transformation. [30] In a 2013 study, there was a 43.5-47.1% rate of malignant progression of aneuploid lesions, although it must be stated that not all such aneuploid leukoplakias behave in such a manner. [31] In a study of oral premalignant conditions with brushed and biopsy samples, it was found that a loss of heterozygosity at chromosome 9p had a significant association with malignant transformation. In such cases, a corresponding and additional mutation in TP53 dictates long-term, strict follow up, and, with observable changes, within or adjacent to the leukoplakia, a new biopsy is recommended for further genetic analysis. [32] Finally, those cases of leukoplakia at high risk for malignant transformation have been associated with aberrant promoter methylation sequences involving several genes, with significantly greater numbers of methylated sequences in dysplastic leukoplakias compared with those without such characteristics. [33]
Among tobacco chewers, epidermal growth factor receptor (EGFR) and Wnt signaling pathway proteins have shown massive overexpression. Furthermore, cells that were structurally abnormal tended to overexpress these oncoproteins. [34]
-
Homogeneous leukoplakia.
-
Erythroleukoplakia.
-
Verrucous or nodular leukoplakia.
-
Carcinoma referred to as a leukoplakia.
Tables
Issue |
|
No Serious Concern |
Concern: Consider Referral to Specialist if Clinician or Patient Concerned, Especially if Multiple Issues Apply |
Serious Concern: Referral to a Specialist |
Historical Features |
Size |
No change |
No reduction in size, even after eliminating trauma to lesion after 10-14 days |
Increasing size, even after eliminating trauma to lesion after 10-14 days |
|
Chronology |
Lesion heals |
No resolution over brief observation period |
Rapid symptom onset Solitary lesion or change in one area of lesion Lesion persisting 3 weeks or longer Persistent ulceration Persistent swelling Loosening of a tooth Nonhealing tooth extraction socket |
|
Neurological |
None |
Lack of pain |
Pain Dysphagia Odynophagia Otalgia Numbness/paresthesia Speech or voice change |
|
Weight |
Normal |
No weight loss |
Weight loss |
History |
Lifestyle Habits |
None |
Tobacco consumption mild/moderate Betel quid or khat consumption mild/moderate Marijuana consumption mild/moderate UV light exposure mild/moderate (lip surface exposure Late-onset sexual debut Few or moderate numbers of lifetime sexual partners |
Tobacco consumption high Betel quid or khat consumption high Alcohol consumption high Marijuana consumption mild/moderate UV light exposure high Early sexual debut Numerous lifetime sexual partners |
|
Medical History |
Clear |
Deficiencies of iron or vitamins A, C, or E Diabetes Discoid lupus erythematosus Dyskeratosis congenita Epidermolysis bullosa Fanconi anemia High-risk human papillomavirus infection Immune defects, including HIV/AIDS or chronic candidosis Medications: Immunosuppressants, antihypertensives Periodontitis, poor hygiene Plummer-Vinson syndrome Scleroderma Xeroderma pigmentosum |
Deficiencies of iron or vitamins A, C, or E Diabetes Discoid lupus erythematosus Dyskeratosis congenita Epidermolysis bullosa Fanconi anemia High-risk human papillomavirus infection Immune defects, including HIV/AIDS or chronic candidosis Medications: Immunosuppressants, antihypertensives Periodontitis, poor hygiene Plummer-Vinson syndrome Scleroderma Xeroderma pigmentosum |
Examination and Imaging |
Potentially Malignant Disorder |
None |
Leukoplakia Lichen planus/lichenoid mucositis Oral submucous fibrosis |
Erythroplakia Leukoplakia; speckled or verrucous Lichen planus/lichenoid mucositis; unilateral |
|
Lesion Features |
Equivocal |
White patch (leukoplakia) Lichen/lichenoid Oral submucous fibrosis |
Red patch (erythroplakia) Mixed red and white patch (erythroleukoplakia/speckled leukoplakia) Granular surface Rolled, elevated margins Ulceration Induration |
|
Cervical Lymph Nodes |
No enlargement |
Possible enlargement |
Enlarged, firm, fixed, nontender, asymmetric |
|
Imaging |
No abnormality |
Any bone density change |
Poorly defined, uncorticated, irregular radiolucency Lamina dura loss Teeth displaced and/or resorbed Pathological fracture |
