Pathological Features

It should be stressed from the outset that the terms leukoplakia and erythroplakia are clinical and descriptive terms, referring to the appearance of the mucosa as a white (leuko) or red (erythro) patch. These terms, particularly leukoplakia, were widely used in the older reports, including seminal prospective studies establishing their potential for developing into overt cancer. However, even when defined clinically, these are diagnoses of exclusion, as they can be reproduced by inflammatory conditions. More importantly, in series controlling for histology, it has been shown that the degree of cytoarchitectural alterations present in the mucosa predicts the risk of progression. Thus, from a pathologist's standpoint, the terms leukoplakia and erythroplakia can be considered descriptive terms of the gross morphology of these lesions, whose identifying features rest on their microscopic appearance, namely on the presence and extent of dysplasia. Thus, histological features of UADT lesions, including their classification and their molecular features, are treated first. This is followed by a description of their clinical features, the correlation existing between histological and clinical classifications (i.e., gross and microscopic features), and their risk of progression.

A. Definitions

Discussion of the histological features of the preinvasive lesions of the upper aerodigestive tract is not possible without a definition of the morphogical nomenclature currently used. A short description of commonly encountered histological terms is provided, describing pathological changes affecting the UADT mucosa [10,11].

1. Squamous Metaplasia

Metaplasia describes the replacement of one type of specialized epithelium with another, i.e., replacement of the ciliated, respiratory-type epithelium of the false vocal cord by squamous epithelium. It is a reversible process that may progress into overt dysplasia or revert to normal and may also be seen in association with inflammatory conditions. It differs from dysplasia in that it lacks any cytological atypia.

2. Simple Hyperplasia

Hyperplasia is an increase in thickness of the epithelium, secondary to an increase in one or more of its component layers: the basal layer, the prickly layer (i.e., acanthosis), or the superficial layer (i.e., hyper/parakeratosis), usually a combination of the former with one or two of the latter, without perturbations in maturation and without any accompanying cytological atypia (Figs. 4.2-4.4). Notably, minimal cell crowding and cytological atypia may also occur in association with inflammation (Fig. 4.5).

FIGURE 4.2 Hyperkeratosis. A granular layer is present below the superficial keratinized layer.
FIGURE 4.3 Hyperkeratosis. Extreme thickening of the mucosa is present, secondary to marked accumulation of superficial squames.

3. Dysplasia/Intraepithelial Neoplasia

This is a mucosal alteration characterized histologically by cellular atypia and loss of maturation, which has the biological potential of developing into overt cancer (see Table 4.1).

4. Mild Dysplasia

Cells with slightly abnormal cytological features are present but are limited to the lower third of the epithelium. Orderly maturation into prickly and squamous layers in the upper two-thirds of the epithelium is preserved. Mitoses may be present but are limited to the basal layer and are of normal configuration; keratosis may be present (Figs. 4.6-4.8).

FIGURE 4.4 Parakeratosis. The superficial layer is thickened, secondary to the presence of multiple layers of parakeratotic squames.
FIGURE 4.5 Inflammatory atypia. Minimal nuclear enlargement occurs in the basal and parabasal layers, associated with a mild lymphocytic infiltrate.

5. Moderate Dysplasia

Cells with atypical cytological features occupy the lower two-thirds of the mucosa. Cytological atypia is more pronounced than in mild dysplasia; nucleoli tend to be prominent. Maturation is preserved in the upper third of the mucosa; normal-appearing mitoses may be found in the parabasal and intermediate layers (Figs. 4.9-4.12).

TABLE 4.1 Histological Criteria Used in the Grading of Dysplasia

Cytological atypia

Increased N/C ratio, presence of nucleoli, hyperchromasia, pleomorphism

Mitotic activity

Increased number and level of mitoses within the mucosa; presence of abnormalities in the mitotic spindle, i.e., tripolar mitoses

Abnormal maturation and polarity

Decreased ratio between the differentiated component, composed of the prickly and squamous layers, and the undifferentiated component, composed of atypical cells. Also reflected by the occurrence of premature keratinization within the epithelium rather than at its luminal surface

FIGURE 4.9 Moderate dysplasia. Dysplastic cells, including forms with giant and multinucleated nuclei, are limited to the lower two-thirds of the epithelium. Progressive and orderly maturation occurs in the superficial layers.

FIGURE 4.6 Low-grade dysplasia (mild). Slight enlargement and crowding of the basal layer, with progressive and orderly maturation in the upper two-thirds of the mucosa.

6. Severe Dysplasia

Atypical cells, showing marked nuclear abnormalities and prominent mitotic activity, occupy more than two-thirds of the epithelium. They are not as crowded and, most importantly, not as cytologically atypical as in CIS. Maturation is preserved, as evidenced by focal superficial squamous maturation and focal preservation of intercellular bridges. Mitoses, including atypical ones, may extend to the upper third of the epithelium. Associated keratosis may be present (Figs. 4.13-4.16).

7. High-Grade Keratinizing Dysplasia

Cells with high-grade cytological features, similar to those found in CIS, occupy the lower two-thirds of the

FIGURE 4.7 Low-grade dysplasia (mild to moderate).

FIGURE 4.9 Moderate dysplasia. Dysplastic cells, including forms with giant and multinucleated nuclei, are limited to the lower two-thirds of the epithelium. Progressive and orderly maturation occurs in the superficial layers.

mucosa; mitoses are frequent, including abnormal ones. Abnormal maturation is highlighted by the occurrence of single cell keratinization or keratin pearl formation within the epithelium rather than at its luminal surface. However, in contrast to "classic" CIS, the uppermost component of the epithelium shows a prominent keratinized layer (Figs. 4.17-4.22).

8. Carcinoma in Situ

Cells with frankly malignant cytological features occupy the whole thickness of the epithelium; squamous differentiation is entirely absent. Abnormal cells have the cytological hallmarks of malignancy, including a high N/C ratio, prominent single or multiple nucleoli, nuclear hyper-chromasia, and pleomorphism. Mitotic figures, including

FIGURE 4.8 Low-grade dysplasia. Dysplastic cells are limited predominantly to the lower third of the epithelium. Progressive and orderly maturation occurs in the parabasal and superficial layers.

FIGURE 4.13 Nonkeratinizing severe dysplasia. Abnormal cells occupy the full thickness of the epithelium. Minimal differentiation is preserved as parakeratotic squames in the surface of the epithelium.

FIGURE 4.10 Moderate dysplasia. Accumulation of abnormal cells is limited to the lower two-thirds of the mucosal thickness.

atypical ones, are frequent and extend throughout the entire mucosa, including its upper third. By definition, the changes are limited to the epithelium and stromal invasion is absent (Figs. 4.23^1.25).

B. Histological Classification

Microscopic grading of preneoplastic lesions of the UADT is of paramount importance biologically and clinically, as the probability of malignant progression into invasive cancer of these lesions is dictated by their grade. This correlation, which is discussed more extensively later, highlights the importance of obtaining a biopsy of all suspect lesions and the priority to be given to microscopic over clinical examination.

The grading system, as described by the WHO [10,11], follows criteria similar to those accepted for other organs,

FIGURE 4.1 1 Moderate dysplasia. Superficial maturation is evident as a layer of spindle-shaped, parakeratotic squames, arranged parallel to the basement membrane.

FIGURE 4.1 2 Low-grade dysplasia (mild to moderate). Abnormal cells occupy the lower two-thirds of the mucosa. Cytological atypia s minimal.

particularly the cervix uteri [12]. Cervical preneoplastic lesions have been studied extensively and have represented for years a standard histological model of squamous preneoplastic lesions. Thus the grading criteria applied to the cervix have been extended to all other squamous

FIGURE 4.13 Nonkeratinizing severe dysplasia. Abnormal cells occupy the full thickness of the epithelium. Minimal differentiation is preserved as parakeratotic squames in the surface of the epithelium.

4. Preneoplastic Lesions

FIGURE 4.14 Nonkeratinizing severe dysplasia.

FIGURE 4.16 Nonkeratinizing severe dysplasia. Dysplastic cells occupy more than two-thirds of the thickness of the epithelium; however, keratinization is observed in the most superficial portions of the epithelium.

preneoplastic lesions, including those of the UADT. This grading system relies on the extent of distribution of the abnormal cells within the epithelium. These are limited to the lower third of the epithelium in mild dysplasia, extend to about two-thirds in moderate dysplasia, and to more than two-thirds of the epithelium in severe dysplasia. The difference between severe dysplasia and CIS is that abnormal cells in CIS have higher grade and frankly malignant cytological features. In addition, in CIS they involve the entire epithelium, including its most apical component and thus a complete lack of maturation/differentiation is present. Lesser grade cytological features and some maturation, however, characterize severe dysplasia [10,11]. Several authors have stressed that the etiopathogenetic factors associated with dysplasia and squamous cancer of the upper aerodigestive tract (i.e., alcohol and smoking) and cervix (HPV infection) are different [13]. Furthermore, it has been pointed out that UADT dysplastic lesions may show unique morphological features not seen in cervical dysplasia. Namely, superficial maturation may be seen in association with high-grade cytological features in the lower third or two-thirds of the mucosa. Thus, the mere application of criteria used for the cervix to the UADT preneoplastic lesions would result in an underassessment of their grade [14,15], Two main classification schemes in alternative to the WHO system have been proposed [13,16-19], They are both characterized by an emphasis on cytological features rather than the relative ratio

FIGURE 4.15 Nonkeratinizing severe dysplasia. Dysplastic cells occupy the full thickness of the epithelium. Differentiation is preserved focally as a thin layer of parakeratotic, strongly eosinophilic squames on the surface of the epithelium.

FIGURE 4.1 7 High-grade (severe) keratinizing dysplasia. Maturation is preserved, as keratinization occurs focally; however, this is associated with marked cytological atypia.

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