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11 – Leukoplakia, Oral Dysplasia, and Squamous Cell Carcinoma

Chapter Contents
  Leukoplakia, Erythroplakia, and Dysplasia 230
  Human Papillomavirus–Associated Apoptotic Dysplasia 241
  Squamous Cell Carcinoma 243
Leukoplakia, Erythroplakia, and Dysplasia

The term oral dysplasia is synonymous with intraepithelial neoplasia as used when discussing the cervix. The equivalent terms squamous intraepithelial neoplasia and oral intraepithelial neoplasia have not to date been universally accepted. The diagnostic term epithelial atypia is sometimes used interchangeably with epithelial dysplasia and this causes confusion; reactive epithelial atypia should always be reported as such. Diagnosis of dysplasia when there is reactive epithelial atypia may account for why some so-called dysplastic lesions regress over time.

Leukoplakia is not any white plaque but rather a white plaque that does not conform clinically or histopathologically to any specific disease and cannot be attributed to reactive, frictional, or traumatic causes. As such, it is a clinical term only and is used when other specific histopathologic and clinical entities are excluded (especially frictional keratoses [see  Chapter 10]). Leukoplakia is the most common precursor lesion before invasive cancer develops.

Development of Invasive Carcinoma

      Of all leukoplakias, 9% to 37% (the most recent figure being 47%) represent dysplasia, carcinoma in situ, or invasive carcinoma at time of biopsy.
      Over time, 16% to 36% of dysplasias develop invasive carcinoma.
      Over time, up to 16% of benign hyperkeratosis without dysplasia will develop dysplasia and/or carcinoma.
      The highest incidence of malignancy is on the ventral tongue, floor of mouth, and soft palate, which are all nonkeratinized sites.
      Over time, 60% to 100% of proliferative leukoplakias develop carcinoma.

Clinical Features

      All forms of leukoplakia are more often seen in older individuals. Correlation of histopathologic findings with clinical appearance of lesions is of the utmost importancce in the accurate diagnosis of dysplasia.

Localized Leukoplakia

      Localized leukoplakia (at a single site) is more common in men and is strongly associated with smoking; leukoplakia are identified:
      Homogeneous leukoplakia is a uniform white plaque, at least partially well-demarcated, with or without fissuring (Fig. 11-1, A and B).
      Nonhomogeneous leukoplakia has verrucous/nodular and erythroplakic areas; it has a higher frequency of developing into dysplasia or carcinoma; erythroleukoplakia is more likely to be misdiagnosed clinically as lichen planus because of its red and white character; although typical reticulations are not present and it is unilateral, demarcation is usually best seen around the white/keratotic areas of the lesion (Fig. 11-2; see Fig. 11-1).

      Verrucous hyperplasia of buccal mucosa may be associated with an areca nut habit.

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FIGURE 11-1  A, Homogeneous leukoplakia: patient had been followed for years with multiple biopsies showing hyperkeratosis without dysplasia, as the lesion gradually expanded to involve his entire right ventral tongue and part of the floor of mouth; note sharp demarcation. B, Homogeneous leukoplakia: well-demarcated white plaque with slight fissuring; histologically, hyperkeratosis and acanthosis, unlikely to be reactive. C, Nonhomogeneous leukoplakia: thick and thin areas of keratosis with an area of ulceration (yellow plaque); histologically dysplastic. D, Nonhomogeneous leukoplakia: well-demarcated plaque with fissures and thick and thin keratosis; histologically dysplastic. E, Nonhomogeneous erythroleukoplakia of the gingiva: histologically, an invasive squamous cell carcinoma.

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FIGURE 11-2  Representation of the clinical and likely corresponding histopathologic findings in leukoplakia.
(Modified from Bouquot JE, Gnepp DR. Laryngeal precancer: a review of the literature, commentary, and comparison with oral leukoplakia. Head Neck. 1991;13:488-497.)

Proliferative Leukoplakia

      Proliferative form is multifocal or extensively affects contiguous sites and often affects gingiva.
      More common in women, it is not strongly associated with smoking; it is present and progressive over 10 to 20 years.
      Homogeneous forms are uncommon; most are nonhomogeneous and usually verrucous/nodular or erythroleukoplakic (Fig. 11-3).

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FIGURE 11-3  Proliferative erythroleukoplakia from one patient. A, Red and white plaque on the left buccal mucosa; fissured white plaques are focally demarcated. B, Red and white fissured plaque on the right buccal mucosa, not well-demarcated. C, Red and white fissured plaques on the ventral tongue and lower labial mucosa, not well-demarcated. D, Red and white plaques of the palate. Patient developed invasive squamous cell carcinoma.


      Erythroleukoplakic form is often clinically misdiagnosed as lichen planus because of multifocality and bilaterality; demarcation is usually best seen around the white/keratotic areas of the lesion, which may show fissuring.
      Erythroplakia appears as a velvety red plaque, usually painless; it is much less common than leukoplakia; more than 90% of these lesions are dysplastic or malignant at the time of diagnosis (Fig. 11-4).

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FIGURE 11-4  Erythroplakia of the palate; histologically, carcinoma in situ.

Etiopathogenesis and Histopathologic Features

Risk factors for localized leukoplakia (excluding the lip where lesions are usually related to actinic damage) are likely the same as for squamous cell carcinoma: cigarette smoking, excessive alcohol consumption, areca nut habit, history of cancer and cancer therapy, history of prolonged immunosuppression, family history of cancer, and age; risk factors for proliferative leukoplakia are less well-defined. Human papillomavirus (HPV) is associated with apoptotic dysplasias (see later). Mutations of genes on 3p, 9p, and 17 seen in squamous cell carcinomas have not been consistently found in oral dysplasia.

Architectural Evidence of Dysplasia

Features of dysplasia that occur in the absence of, or with minimal evidence of, cytologic dysplasia are often observed in clinical lesions of verrucous and proliferative leukoplakias (Table 11-1)
      Bulky epithelial proliferation, especially if endophytic and without leukocyte exocytosis or spongiosis (Figs. 11-5 to 11-7); many of these are thick plaques or masses clinically
      Papillary or verrucous epithelial proliferation, broad based, in an exophytic or endophytic configuration, often bulky (Figs. 11-8 to 11-10)
      Bulbous or drop-shaped rete ridges (Fig. 11-11)
      Sharp demarcation of the keratotic area from the adjacent normal epithelium and “skip” areas of normal mucosa sandwiched by hyperkeratotic or dysplastic epithelium (Figs. 11-12 and 11-13)
      Marked hyperorthokeratosis with epithelial atrophy (usually sharply demarcated) in the absence of inflammation and/or not representing a specific disease entity (such as atrophic or treated lichen planus) should be viewed with suspicion; not all dysplasias are hyperplastic lesions
      Sixteen percent of so-called benign hyperkeratoses developing into carcinoma owing to underdiagnosis of these lesions with minimal cytologic atypia.

TABLE 11-1   -- Histopathologic Features of Dysplasia
Architectural features
      Bulky and/or endophytic proliferation
      Verrucous or papillary epithelial proliferation
      Bulbous or drop-shaped rete ridges
      Sharply demarcated keratinization, usually multifocal with “skip” areas
      Hyperkeratosis with atrophy in the absence of inflammation, usually sharply demarcated
Organizational features
      Loss of stratification and polarity
      Basal cell hyperplasia
      Mitoses (even if normal-appearing) beyond the suprabasal keratinocytes
      Keratin pearl formation, usually at tips of rete ridges
      Basal cell hyperplasia
Cytologic features (those noted on exfoliative cytology)
      Increased nuclear : cytoplasmic ratio or enlarged nuclei
      Variation in nuclear shape (pleomorphism) and size (anisonucleosis)
      Variation in cell shape (pleomorphism) and size (anisocytosis)
      Coarse chromatin and prominent nucleoli
      Abnormal mitoses
      Dyskeratosis or keratin pearl formation
      Cells with glassy appearance of cytoplasm

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FIGURE 11-5  Hyperparakeratosis with dysplasia. A, Bulky epithelial proliferation and cells with glassy cytoplasm. B, Slight basal cell hyperplasia.

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FIGURE 11-6  Hyperparakeratosis with dysplasia (floor of mouth). A, Bulky epithelial proliferation with mild cytologic atypia with focal area of epithelial atrophy. B, Bulky epithelial proliferation with mild cytologic atypia, not reactive in nature. C, Area of atrophy exhibiting moderate epithelial dysplasia; however, entire lesion should be considered dysplastic.

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FIGURE 11-7  Bulky atypical squamous proliferation with dysplasia. A, Bulbous confluent rete ridges with slightly endophytic pattern; note normal thickness of epithelium on left. B, Loss of normal stratification with dysmaturation, dyskeratosis, and discohesion. C, Basaloid cell hyperplasia with focus of dyskeratosis, slight nuclear atypia.

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FIGURE 11-8  Verrucous hyperplasia with dysplasia. A, Minimal-to-severe epithelial dysplasia (center). B, Minimal dysplasia (skip area) bracketed by severe dysplasia; note change in nature of keratin and organizational disarray. C, Discohesion, dyskeratosis, and nuclear pleomorphism.

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FIGURE 11-9  Verrucous hyperplasia with dysplasia. A, Hyperorthokeratosis, hypergranulosis, and verrucous epithelial proliferation showing sharp demarcation from surrounding normal epithelium; note early, thinly keratotic area sandwiched by hyperorthokeratotic areas. B, Abrupt keratinization corresponding to sharp demarcation clinically. C, Mild dysplasia involving the lower one third only. D, Another area shows insignificant dysplasia but with similar architecture.

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FIGURE 11-10  Verrucous hyperplasia with dysplasia. A, Severe dysplasia and lymphocytic band at interface. B, Severe dysplasia with dyskeratosis and cells with glassy cytoplasm. C, Keratin pearl at base of epithelium, dyskeratosis, and cells with glassy cytoplasm.

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FIGURE 11-11  Mild dysplasia. A, Drop-shaped rete ridges with basal cell hyperplasia. B, Basal cell hyperplasia and cells with pleomorphic nuclei and mitoses.

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FIGURE 11-12  Hyperorthokeratosis with minimal-to-mild dysplasia. A, Compact hyperorthokeratosis and abrupt transition to normal mucosa (right). B, Mild basal cell hyperplasia and surface undulations. C, Sharp demarcation of dysplastic epithelium and insinuation of dysplastic cells between normal-appearing keratinocytes.

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FIGURE 11-13  Hyperorthokeratosis with moderate epithelial dysplasia: abrupt transition between keratotic dysplasia with discohesive and pleomorphic cells and normal mucosa, corresponding to sharply demarcated clinical lesion.

Organizational Evidence of Dysplasia

Maturation disarray or dysmaturation, and loss of stratification and polarization characterized by basal cell hyperplasia (also cytologic evidence of dysplasia), discohesion, increased mitotic activity beyond immediate suprabasilar cells, and keratin pearls within tips of rete ridges may be evident.

Cytologic Evidence of Dysplasia

Cytologic features are similar to those at other mucosal sites and are readily noted on exfoliative cytology (see Table 11-1); reactive epithelial atypia from inflammation may show the same features to a lesser degree.
      Graded mild (less than one third of the thickness of the epithelium involved by dysplasia), moderate (one third to two thirds), and severe (more than two thirds, not including carcinoma in situ) by convention (Figs. 11-14 to 11-16); carcinoma in situ shows full thickness involvement (Fig. 11-17); presence of a lymphocytic band at the interface is common and does not necessarily represent preexisting lichen planus; this is likely a T cell response to altered antigens on dysplastic keratinocytes.
      Involvement of ducts by dysplasia must be documented, because deep margins may not be clear of dysplasia if deep portions of duct are involved; this feature is associated with an increased rate of local recurrence (Figs. 11-18 and 11-19).
      Molecular markers and presence of high-risk HPV is not consistently predictive of subsequent development of invasive carcinoma.

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FIGURE 11-14  Mild epithelial dysplasia. A, Hyperparakeratosis and mild epithelial dysplasia. B, Basal cell hyperplasia in the absence of inflammation involving less than one third the thickness of epithelium.

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FIGURE 11-15  Moderate epithelial dysplasia. A, Bulbous rete ridge and basal cell hyperplasia and discohesion (right). B, Basal cell hyperplasia and mitoses. C, Area bordering on severe dysplasia with discohesion, high mitoses, cells with increased nuclear-to-cytoplasmic ratio, and hyperchromatic nuclei.

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FIGURE 11-16  Hyperparakeratosis and severe epithelial dysplasia. A, Eosinophilic cells with glassy cytoplasm, bulbous rete ridges, and lymphocytic band. B, Discohesion, nuclear pleomorphism, hyperchromatism, and abnormal mitoses.

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FIGURE 11-17  Carcinoma in situ. A, Budding rete ridges, dysplastic cells involving full thickness of epithelium, and lymphocytic infiltrate. B, Basal cell hyperplasia, cells with large nuclei, and many high mitotic figures.

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FIGURE 11-18  Moderate-to-severe epithelial dysplasia involving excretory duct. A, Sharply demarcated hyperorthokeratosis with dysplasia involving upper portion of duct. B, Surface exhibits discohesion, basal cell hyperplasia, and nuclear hyperchromatism. C, Dysplasia (basal cell hyperplasia) of duct.

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FIGURE 11-19  Moderate-to-severe epithelial dysplasia involving excretory duct. A, Overlying epithelium exhibits basal cell hyperplasia; one duct is involved by dysplasia. B, Pleomorphic and dysplastic cells involve the full thickness of the duct.

Differential Diagnosis

      Reactive atypia is sometimes difficult to differentiate from true dysplasia, especially in the presence of reepithelialization and healing ulceration; if one cannot be sure, suggest using the phrases likely reactive, unsure if reactive, unlikely reactive, or suspicious for dysplasia to guide patient management.
      Lichen planus or lichenoid mucositis with reactive atypia tends to show squamatization of basal cells (instead of basal cell hyperplasia) and colloid body formation; multinucleated epithelial cells with finely dispersed chromatin and abundant cytoplasm are often seen in reactive lesions (Fig. 11-20).
      Candidiasis may show significant reactive atypia; to complicate matters, dysplastic epithelium is often colonized by Candida, likely because of breakdown of immune surveillance in some cases.

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FIGURE 11-20  Lichenoid mucositis with reactive epithelial atypia. A, Hyperorthokeratosis and lymphocytic band at the interface. B, Squamatized basal cells, colloid bodies, and reactive epithelial atypia with multinucleated epithelial cells. C, Squamous cells exhibit reactive atypia abutting the typical subbasal cleft.

Management and Prognosis

      Multiple biopsies should be performed for nonhomogeneous leukoplakia and proliferative leukoplakia.
      All dysplasias, including mild dysplasias (not reactive atypia) should be carefully followed or excised/ablated, depending on the clinical situation (e.g., high-risk site and high-risk history); recurrence occurs in 30% to 60% of cases.
      Cases that are suspicious for dysplasia because of architectural abnormalities without cytologic evidence of dysplasia, location at high-risk sites, or sharp demarcation may be candidates for narrow excision or ablation, unless morbidity is unacceptable.
      Lifetime follow-up is recommended.


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