Premalignant lesions of the upper aerodigestive tract: Biomarkers of genetic alterations, proliferation, and differentiation

The normal distribution of cell division in squamous mucosa is in the basal or adjacent suprabasal cell layers. Migration of cells toward the epithelial surface results in cell differentiation, most often expressed by high molecular weight keratin intermediate filaments and components of the cornified envelope, including “involucrin.” These latter expressions of terminal differentiation are common in keratinizing dysplasia and invasive squamous cell carcinomas. However, they are less common in the non‐keratinizing dysplasias, which fail to express evidence of epithelial maturation. Cell proliferation occurs in or near the basal layer in normal or reactive/reversible hyperplasias. In dysplasia (both keratinizing and non‐keratinizing), cell proliferation is observed at all levels of the epithelium. Concomitant with these abnormalities in proliferation and differentiation are nuclear changes characterized by large hyperchromatic nuclei. The enlarged nuclei reflect increased DNA content, as documented by flow cytometry and image analysis techniques. DNA aneuploidy represents a spectrum of genomic alterations reflecting steps toward the progression to invasive carcinoma, which for the most part, have not yet been identified.