Incorporation of differentiated dysplasia improves prediction of oral leukoplakia at increased risk of malignant progression

Abstract

Oral leukoplakia is the most common oral potentially malignant disorder with a malignant transformation rate into oral squamous cell carcinoma of 1-3% annually. The presence and grade of World Health Organization defined dysplasia is an important histological marker to assess the risk for malignant transformation, but is not sufficiently accurate to personalize treatment and surveillance. Differentiated dysplasia, known from differentiated vulvar intraepithelial neoplasia, is hitherto not used in oral dysplasia grading. We hypothesized that assessing differentiated dysplasia besides World Health Organization defined (classic) dysplasia will improve risk assessment of malignant transformation of oral leukoplakia. We investigated a retrospective cohort consisting of 84 oral leukoplakia patients. Biopsies were assessed for dysplasia presence and grade, and the expression of keratins 13 (CK13) and 17, known to be dysregulated in dysplastic vulvar mucosa. In dysplastic oral lesions, differentiated dysplasia is as common as classic dysplasia. In 25 out of 84 (30%) patients, squamous cell carcinoma of the upper aerodigestive tract developed during follow-up. Considering only classic dysplasia, 11 out of 56 (20%) patients with nondysplastic lesions progressed. With the incorporation of differentiated dysplasia, only 2 out of 30 (7%) patients with nondysplastic lesions progressed. The risk of progression increased from 3.26 (Hazard ratio, p = 0.002) when only classic dysplasia is considered to 7.43 (Hazard ratio, p = 0.001) when classic and differentiated dysplasia are combined. Loss of CK13, combined with presence of dysplasia, is associated with greater risk of malignant progression (p = 0.006). This study demonstrates that differentiated dysplasia should be recognized as a separate type of dysplasia in the oral mucosa and that its distinction from classic dysplasia is of pathological and clinical significance since it is a strong (co) prognostic histopathological marker for oral malignant transformation. In oral lesions without dysplasia and retained CK13 staining the risk for progression is very low.

Genes and pathways monotonically dysregulated during progression from normal through leukoplakia to gingivo-buccal oral cancer

“…Oral leukoplakia is the most common precancerous lesion in the oral cavity with a global prevalence of 2–3% 6 . A recent study 7 on about 5000 individuals with leukoplakia has estimated that (a) only about one-third of individuals with leukoplakia develop oral cancer, and (b) the vast majority of individuals with leukoplakia who are found to progress to oral cancer develop the disease within 1 year of diagnosis of leukoplakia.…”

An active surveillance program in oral preneoplasia and translational oncology benefit

“…Wils et al recently reported on differentiated dysplasia, which is a subtype of dysplasia that is separate from the classic WHO definition and may be a more sensitive indicator to rule out concerning oral lesions. This dysplasia is characterized by “a basal layer of small cells with hyperchromatic or open nuclei with small nucleoli with an abrupt transition to suprabasal large cells with abundant, eosinophilic cytoplasm with differences in eosinophilia, intercellular edema, with clearly visible desmosomes, and large open nuclei with prominent nucleoli.” 13 In their study, when classic (WHO) dysplasia was ruled out, 11 of 56 progressed to cancer, but only two of 30 progressed to cancer when differentiated dysplasia was also ruled out. This is a new application to oral leukoplakia and it is not clear if it will become applied widely.…”

“…Despite this, clinicians should be aware of some of these previous studies as they do provide information on leukoplakia pathophysiology. In a study by Wils et al, patients with no histological dysplasia who retained cytokeratin 13 (CK13) staining had significantly lower risk of progression to cancer 13 . Podoplanin is a lymphatic endothelial marker expressed in some cancers like esophageal cancer.…”

Resection Margins in Head and Neck Cancer Surgery: An Update of Residual Disease and Field Cancerization

“…Standard clinical policy is to take a biopsy to exclude invasive growth, which also allows grading for epithelial dysplasia on the basis of morphological abnormalities. Dysplasia is the best predictor of malignant transformation of leukoplakia, particularly when ‘differentiated dysplasia’, a novel morphological abnormality, is added [ 40 ].…”