and specialization. The stratum basale is constituted by cuboidal cells with a high N/C ratio, resting on the basement membrane (Fig. 4.1). Molecular data show that they are the only cell type that expresses proliferation-associated antigens [1] and the RNA component of telomerase [2] within the normal mucosa. By replacing committed cells, which undergo terminal differentiation in the more superficial layers of the epithelium, these basal cells assure the turnover of the epithelium and thus have the role of stem cells [3]. In keratinized epithelium, the superficial layer is constituted entirely by anucleated cells, showing accumulation of intermediate filaments, whereas in nonkeratinized epithelium, small nuclei are still retained. Furthermore, in keratinized epithelium, an intermediate layer may be present between the keratin layer and the prickly layer, similar to the epidermis, characterized by large intracellular granules, called stratum granulosum. Regional variations in the composition of the epithelium, including its degree of keratinization, reflect differences in the extent of mechanical stress during mastication, which in turn depends on the resiliency of the exposed areas. Thus, the squamous (masticatory) mucosa of the gingiva and hard palate, fastened to the underlying bone by heavy collagen bundles, not allowing it to stretch it, is keratinized. The thickness of the stratum granulosum is also more pronounced in the hard palate. Areas of the oral cavity, such as lips, soft palate, cheeks, and floor of mouth, characterized by higher resiliency and subject to lesser mechanical stress, are lined by nonkeratinized mucosa. Some individuals show an anatomic variant of this distribution, characterized by keratinization occuring in the malar mucosa, along a line starting from the labial commissure and running parallel to the occlusion line of premolars and molars. This line is visible clinically as a white line and is designated linea alba.

The structure of the interface with the underlying stroma also reflects the amount of mechanical stress to which the

FIGURE 4.1 Normal squamous mucosa. Notice bland cytological features and progressive and orderly maturation from the basal to the superficial layer.

mucosa is subject. Thus, the buccal mucosa has prominent mucosal ridges, anchoring it to a heavily collagenized lamina propria. In contrast, areas protected from stress, such as the floor of mouth, possess thinner and more shallow rete ridges and a less collagenized lamina propria [4].

The mucosa of the tongue has peculiar histological features, pertaining to its function as a taste organ, which are of no relevance in this setting. In its posterior third, the lingual mucosa becomes enriched with lymphoid tissue, part of the mucosa-associated lymphoid tissue (MALT) of the UADT.

The degree of keratinization, thickness, presence of pigments, and degree of vascularization of the mucosa and its lamina propria all affect the color of the mucosa, an issue of relevance in correlating the clinical appearance of mucosal lesions with its microscopic composition, as discussed later.

The oral cavity hosts minor salivary glands within its submucosa. Notably, dysplasia and carcinoma in situ (CIS) can involve the acini as well as the excretory ducts of minor salivary glands, mimicking invasive carcinoma [5].

B. Pharynx

The pharynx is divided into three anatomical compartments: oropharynx, nasopharynx, and hypopharynx. The oropharynx and hypopharynx are lined by stratified, nonkeratinized squamous epithelium. The submucosa contains seromucinous glands and aggregates of lymphoid tissue. The nasopharynx is lined with approximately 60% stratified, nonkeratinized squamous epithelium and with approximately 40% ciliated, respiratory-type epithelium. The latter predominates in the posterior nares and in the roof of the posterior wall, whereas the remaining areas reveal an alternation of the two types of epithelia. Notably, at the transition between the two types, the mucosa assumes an "intermediate" or "transitional" appearance that may mimic dysplasia [6]. Similar features are observed at the transition betweeen squamous and respiratory epithelium in the larynx in normal conditions [6], and during the process of squamous metaplasia in the bronchial-ciliated epithelium, in response to irritants [7].

C. Larynx

The type of epithelial lining of the larynx changes according to the location and shows an alternation of ciliated, respiratory-type and squamous epithelium. The supraglottic compartment (extending from the tip of the epiglottis to the true vocal cord) shows respiratory-type epithelium, which merges into squamous epithelium in the posterior surface of the epiglottis superiorly and, inferiorly, at the glottis (composed of the true vocal cords and the anterior commissure). Thus, the false vocal cords are lined by respiratory epithelium, whereas the true vocal cords are lined by squamous epithelium. The squamous epithelium merges into respiratory mucosa at the lower border of the true vocal cord, covering the subglottic larynx (the portion of larynx comprised between the lower border of the true vocal cord and the first tracheal ring) and blends inferiorly in the respiratory epithelium of the trachea.

The respiratory epithelium is a ciliated, pseudostratified epithelium. Its basal layer is composed of basal cells, connected to the basement membrane by hemidesmosomes, which do not reach to the lumen. They have a high nucleus/ cytoplasmic ratio and, like in squamous mucosa, represent the regenerative component of the epithelium. The differentiated cells warding the luminal surface are composed of ciliated, brush, and goblet cells, allowing mucociliary clearance. A minor component of the epithelium, detectable only by performing electron microscopy or special immunohistochemi-cal stains, is constituted by small granular cells. These cells, which are morphologically similar to the basal cells by regular light microscopy, have neurosecretory granules and belong to the diffuse neuroendocrine system [8], Areas between the squamous and the respiratory-type epithelium have a transitional appearance, characterized by progressive flattening of luminal cells, a progressively more elongated shape, and an arrangement parallel to the basement membrane. The mucosa in these areas may assume a relatively disorganized appearance, referred to also as "incomplete metaplasia," which may mimic true dysplasia. However, frank cytological atypia is absent and maturation is preserved [9], In approximately half of smokers, patches of metaplastic squamous mucosa are present in the supraglottic larynx [9].

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