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Leukoplakia, erythroplakia, oral dysplasia, and squamous cell carcinoma


Oral epithelial dysplasia is one of the most challenging entities for a pathologist. This chapter provides histopathologic features for the diagnosis of oral epithelial dysplasia, including HPV-associated oral dysplasia and guidance on how to distinguish dysplastic lesions from lesions exhibiting reactive atypia. It provides histopathologic features on the variants of oral carcinoma including carcinoma in children.

Leukoplakia, erythroplakia, and dysplasia

Leukoplakia and its clinical variants are the most common precursor lesions of invasive squamous cell carcinoma with erythroplakia a distant second. The term oral epithelial dysplasia is synonymous with intraepithelial neoplasia as used in the cervix. The terms squamous intraepithelial neoplasia and oral intraepithelial neoplasia have been proposed but are not universally accepted at this time. The term epithelial atypia is sometimes used interchangeably with epithelial dysplasia and this often causes confusion. Reactive epithelial atypia should be reported as such, and epithelial atypia that is not within the spectrum of reactive change should be reported as either epithelial dysplasia if that is what it is, or that it is uncertain whether the atypia represents reactive change or dysplasia, understanding that it is sometimes extremely difficult to differentiate between the two. Reviewing clinical images is extremely helpful in such instances.

According to the World Health Organization, leukoplakia is “a predominantly white plaque of questionable risk having excluded other known diseases or disorders that carry no increased risk for cancer.” As such, it is not any white plaque but one that does not conform clinically or histopathologically to a defined disease (e.g., primary candidiasis or lichen planus), cannot be attributed to reactive, frictional, or traumatic causes, and is highly associated with dysplasia and the development of cancer. It is a clinical term of exclusion and such keratotic lesions must always be biopsied because leukoplakia is the most common precursor of invasive carcinoma.

Clinical findings

  • All forms of localized leukoplakia and erythroplakia are seen more often in older individuals. The exception is leukoplakia associated with syndromes such as dyskeratosis congenita or Li Fraumeni syndrome which may present in the second and third decades of life.

  • The sites with the highest incidence of development of squamous cell carcinoma are the ventral tongue, floor of mouth, buccal mucosa, and gingiva. Although the soft palate is an uncommon site for leukoplakia, it has a high prevalence of dysplasia or carcinoma when it does occur.

  • All lesions should be palpated to evaluate for firmness or induration, which may indicate the presence of an invasive carcinoma.

  • Malignant transformation is associated most strongly with the presence of higher grades of dysplasia because of the sequential accumulation of mutations, and associated clinical factors include nonhomogeneous appearance, large size of lesions, and lesions located on the ventral tongue, floor of mouth, and soft palate.

Localized leukoplakia

Recent data show that of all leukoplakias, approximately 43% to 47% represent dysplasia, carcinoma-in-situ, or invasive carcinoma at the time of biopsy. this higher prevalence of dysplasia (compared with 9%–20% in older studies) may be related to frictional and other reactive keratoses being included in older studies ( Fig. 11.1 ). Most of the other 53% to 57% of cases that do not show cytologic features of dysplasia are likely also dysplastic by applying architectural criteria for dysplasia. They look similar clinically to leukoplakia with dysplasia and these architectural changes are often present adjacent to cytologically dysplastic epithelium suggesting a continuum. Overall, approximately 10% to 18% of localized leukoplakias undergo malignant transformation based primarily on cytologic criteria.

Fig. 11.1, Algorithm for diagnosis and management of keratotic lesions.

Localized leukoplakia (at a single site) is more common in men, especially when it occurs on the ventral tongue and floor of mouth, and is strongly associated with smoking. Two main clinical variants are identified:

  • Homogeneous leukoplakia is a uniform white plaque, at least partially well demarcated, with or without fissuring ( Fig. 11.2 A–D); these have a lower association with the development of dysplasia and invasive carcinoma (1%–2%).

    Fig. 11.2, Homogeneous leukoplakia (A–D). (A) Patient had been followed for years with multiple biopsies showing hyperkeratosis, not reactive, as the lesion gradually expanded to involve his entire right ventral tongue and part of the floor of mouth; note sharp demarcation. (B) Well-demarcated white plaque with slight fissuring; histologically, hyperkeratosis and acanthosis, not reactive. (C) Well-demarcated, of the mandibular gingiva, histopathologically dysplastic. (D) Well-demarcated and fissured leukoplakia of the buccal mucosa, histopathologically dysplastic. (E) Verrucous leukoplakia of the mandibular alveolar ridge mucosa, well-demarcated, histologically dysplastic. (F–H) Erythroleukoplakia. (F) Red and white plaque of the buccal mucosa, histopathologically carcinoma-in-situ. (G) Red and white plaque of ventral tongue, partially demarcated, histopathologically squamous cell carcinoma. (H) Red and plaque of gingiva, histopathologically squamous cell carcinoma.

  • Nonhomogeneous leukoplakia: these plaques have a warty, rough, and verrucous character (verrucous leukoplakia), nodular areas, or red areas (erythroleukoplakia or speckled leukoplakia). Nonhomogeneous leukoplakia has a higher frequency of developing into dysplasia or carcinoma (13%).

  • Verrucous leukoplakia occurs frequently on the marginal gingiva or alveolar ridge mucosa (see Fig. 11.2 E).

  • Erythroleukoplakia (or speckled leukoplakia) may be misdiagnosed clinically as lichen planus because of its red and white appearance, although unequivocal white reticulations are usually not present and it is often unilateral and/or asymmetric with demarcation best seen around the white/keratotic areas of the lesion (see Figs. 11.2 F–H and 11.3 ).

    Fig. 11.3, Representation of the clinical and corresponding histopathologic findings in leukoplakia.

Proliferative (verrucous) leukoplakia

This entity is defined by World Health Organization (WHO) as a distinct form of multifocal leukoplakia characterized by a progressive clinical course, changing clinical and histopathological features and is associated with the highest risk for oral carcinoma development. However, it differs from the more common localized leukoplakia in many aspects.

  • Proliferative leukoplakia is more common in women and is not strongly associated with smoking.

  • It is persistent, tends to recur after removal, and progresses and spreads over decades to involve large areas of the mucosa.

  • Lesions are multifocal or a lesion may extensively affect a single site such as the tongue dorsum (at least 4 cm), or contiguous sites (at least 3 cm), and the gingiva is frequently involved. Similar to localized leukoplakia, proliferative leukoplakia may be homogeneous (uncommon) or nonhomogeneous with fissuring and verrucous/nodular areas referred to as proliferative verrucous leukoplakia , or exhibit erythroleukoplakia, referred to as proliferative erythroleukoplakia. Although some areas may be well demarcated, others may not be ( Figs. 11.4 and 11.5 ).

    Fig. 11.4, Proliferative leukoplakia, from one patient. (A) Ventral and dorsal tongue have fissured demarcated leukoplakia. (B) Maxillary gingiva has poorly demarcated keratosis. (C) Left mandibular lingual mucosa with demarcated and fissured leukoplakia. (D) Anterior lingual gingiva with poorly demarcated leukoplakia. (E) Hard palatal mucosa with faint leukoplakia. (F) Squamous cell carcinoma developed within this subtle palatal leukoplakia.

    Fig. 11.5, 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 lip mucosa, not well demarcated. (D) Red and white plaques of the palatal mucosa. Patient developed invasive squamous cell carcinoma.

  • Proliferative erythroleukoplakia may resemble lichen planus because of bilaterality and multifocality, but reticulations are usually not seen, although trabecular keratotic bands may be encountered. Demarcation and fissuring is almost always present around the keratotic areas.

  • A hallmark of this condition is that early lesions exhibit architectural features of dysplasi namely hyperkeratosis, often epithelial atrophy and/or verrucous architecture with little to no evidence of cytologic dysplasia ( Table 11.2 ).

  • Over time, 50% to 100% of proliferative leukoplakias develop carcinoma.

Erythroplakia

This is a rare condition and over 90% of all erythroplakias exhibit dysplasia, carcinoma-in-situ, or invasive carcinoma at the time of biopsy.

  • Erythroplakia presents as a velvety, granular red plaque that is usually painless and may be indurated ( Fig. 11.6 ).

    Fig. 11.6, (A) Erythroplakia of the left palatal mucosa; histopathologically, carcinoma-in-situ. (B) Erythroplakia of the right maxillary alveolar ridge mucosa, histopathologically invasive carcinoma.

Etiopathogenesis and histopathologic features

Because leukoplakia is the most common precursor to invasive squamous cell carcinoma, the risk factors for localized leukoplakia are the same as for squamous cell carcinoma ( Table 11.1 ). Risk factors for proliferative leukoplakia are less well defined.

TABLE 11.1
Risk Factors for Development of Leukoplakia and Oral Squamous Cell Carcinoma

  • Environmental factors

    • Cigarette smoking

    • Chewing of areca nut and use associated products such as betel quid and paan

    • Use of other tobacco products such as toombak

    • Drinking alcohol especially if associated with smoking

    • Human papillomavirus

    • Sunlight (lip vermilion only)

  • Personal history

    • History of cancer and cancer therapy

    • History of immunosuppression

      • prophylaxis for chronic graft-versus-host disease after hematopoietic cell transplantation

      • prophylaxis against graft rejection for solid organ transplantation

      • HIV/AIDS

    • Autoimmune disease with or without treatment

    • Age

    • History of cancer predilection syndromes such as Li Fraumeni syndrome, dyskeratosis congenita xeroderma pigmentosum, Bloom syndrome, Fanconi anemia, ataxia telangiectasia

  • Family history of cancer especially of head and neck cancer

The role of carcinogens in tobacco is discussed in the section on squamous cell carcinoma. Similar to precancerous lesions in other parts of the body that develop carcinoma over time, oral epithelial dysplasia is the result of cumulative genetic and/or epigenetic events and mutations usually of tumor suppressor genes, leading to increasing severity of dysplasia and finally carcinoma. Aneuploidy has been shown to correlate with development of invasive carcinoma in localized leukoplakias. Loss of heterozygosity in multiple chromosomes (such as in 3p, 4p, 4q, 8p, 9p, 11q, and 17p) is also associated with progression of dysplasia to invasive carcinoma. Some verrucous hyperplasias exhibit loss of heterozygosity involving 3p, 4q, 9p, and 11q. Overexpression of c- erb B-3 protein correlates with increased proliferative cell nuclear antigen labeling index as lesions progress from verrucous hyperplasia to verrucous carcinoma. Stabilizing mutations of TP53 that inhibit degradation of p53 protein result in overexpression of this protein in some oral dysplasias. Data also show that even the cases of leukoplakia that show architectural but not cytologic evidence of dysplasia exhibit similar mutations to lesions of moderate-to-severe dysplasia strongly suggesting that the clinical phenotype of leukoplakia (demarcated lesion) as well as architectural changes are very important diagnostic criteria especially in early lesions. Furthermore, 28% versus 55% of oral squamous cell carcinomas arose in areas of hyperkeratosis without and with dysplasia, respectively.

Lesions of proliferative leukoplakia do not show the same molecular changes as localized leukoplakia and show weak association with aneuploidy, loss of heterozygosity at 9p21, and specific expression of Mcm protein. Concomitant loss of p16 INK4a and p14 ARF occurred in 45% of cases compared with 15% in localized leukoplakia and the gene for granzyme M is highly expressed in proliferative lesions.

Conventional parameters for dysplasia are based on cytologic features best seen at high power and that also are recognizable on cytopathology preparations harvested using a cyto-brush or other equivalent tool. However, gross architectural features noted on low power and organizational disarray noted on intermediate power are just as important, and these may occur in the absence of, or with only minimal cytologic evidence of dysplasia. Some of these features belong in more than one category; for example, basal cell hyperplasia is both a cytologic and organizational feature of dysplasia. No single criterion for the diagnosis of dysplasia is sufficient for the diagnosis, because many of the features of dysplasia may be seen as reactive atypia in inflamed epithelium, especially adjacent to ulcers or associated with candidal infection. Correlation with clinical findings is of the utmost importance for accurate diagnosis when histopathologic features are equivocal for dysplasia; it cannot be overemphasized that cytologic features alone are insensitive for the diagnosis of oral dysplasia.

Finally, there is still no consensus as to how to best grade dysplasia. Most use the traditional mild , moderate , and severe grades depending on the thickness of the epithelium involved, whereas others use low grade and high grade. Each has its own merits and, in general, moderate and severe dysplasia (high-grade dysplasia) show better interexaminer reliability and consistency, and are generally associated with a higher incidence of, or shorter time to, development of carcinoma. On the other hand, both mild dysplasia and hyperkeratosis that are not reactive develop invasive carcinoma in approximately 5% of cases compared to 15% to 25% for all dysplasias. As expected, there is poor interexaminer reliability on grading mild dysplasia and this is likely because reactive atypias are lumped into the category of mild dysplasia especially in cases of candidiasis. However, at this time, neither system of grading dysplasia takes into account gross architectural features of dysplasia, such as demarcation, corrugation, bulky proliferation, and verrucous hyperplasia, that are just as important.

The features of epithelial dysplasia discussed later apply to all leukoplakias whether localized/unifocal or proliferative/multifocal.

Architectural evidence of dysplasia

Architectural features of dysplasia obvious at low-power microscopy, that occur in the absence of, or with minimal evidence of cytologic dysplasia often are observed in both localized verrucous leukoplakia and proliferative leukoplakia ( Table 11.2 ). They may also occur with clear evidence of cytologic dysplasia.

  • Corrugated, papillary, or verrucous hyperplasia, broad-based, in an either exophytic and/or endophytic configuration that is sometimes bulky ( Figs. 11.7–11.10 ). When there is minimal to no dysplasia, the diagnosis of atypical verrucous hyperplasia/squamous proliferation signals to the clinician that this is not a benign verrucous epithelial proliferation.

    Fig. 11.7, Atypical verrucous hyperplasia with mild to no dysplasia (A–D). (A) Hyperkeratosis, hypergranulosis, and verrucous epithelial proliferation showing sharp demarcation from surrounding normal epithelium (right) ; note early, thinly keratotic area sandwiched by markedly hyperkeratotic areas with keratin thickness similar to epithelial thickness. (B) Abrupt keratinization corresponding to sharp demarcation clinically. (C) Mild epithelial dysplasia. (D) A different site with verrucous architecture but no dysplasia. Fissured leukoplakia with hyperkeratosis and epithelial atrophy. (E) Demarcated and fissured leukoplakia of the buccal mucosa. (F) The surface is undulated with troughs corresponding to clinical fissures. (G) Hyperkeratosis with mild epithelial dysplasia and mitotic figures.

    Fig. 11.8, Atypical verrucous hyperplasia. (A) There is endophytic growth and lymphocytes are present beneath the verrucous hyperplasia but not at the edge where there is normal mucosa (left). (B) Rete ridges are bulbous but epithelium overlying fibrovascular cores is attenuated. (C) There is minimal cytologic dysplasia.

    Fig. 11.9, Atypical verrucous hyperplasia with dysplasia. (A) Corrugated surface with parakeratosis and varying degrees of dysplasia. (B) Mild dysplasia in skip segment bracketed by severe dysplasia; note change in nature of keratin and bulbous rete ridges. (C) Dyscohesion, dyskeratosis, increased nuclear:cytoplasmic ratio, and nuclear pleomorphism.

    Fig. 11.10, Atypical verrucous hyperplasia with dysplasia. (A) Marked parakeratosis with papillary/verrucous epithelial hyperplasia and severe dysplasia with lymphocytic band at interface. (B) Severe dysplasia with dyskeratosis and lymphocytic band. (C) Keratin pearl at base of epithelium, dyskeratosis, and cells with glassy cytoplasm.

  • Demarcated hyperkeratosis with or without a corrugated or undulated surface and epithelial atrophy in the absence of inflammation. The thickness of the keratin is often at least half if not more than the thickness of the underlying atrophic epithelium ( Figs. 11.11 and 11.12 ). Demarcation is likely a sign of clonality.

    Fig. 11.11, (A) Demarcated homogeneous and fissured gingival leukoplakia. (B) Biopsy from (A) shows hyperkeratosis where thickness of keratin is more than half the thickness of the atrophic epithelium for gingiva. (C) Hyperkeratosis and epithelial atrophy, not reactive without evidence of dysplasia.

    Fig. 11.12, (A) Demarcated hyperkeratosis of the ventral tongue. (B) Slight basal cell crowding and prominence, not reactive and equivocal for dysplasia.

  • “Skip” segments of normal mucosa sandwiched by hyperkeratotic, parakeratotic, or dysplastic epithelium ( Figs. 11.13 and 11.14 ).

    Fig. 11.13, Hyperkeratosis with skip segments and mild dysplasia. (A) Compact hyperkeratosis and several abrupt transitions to normal mucosa or skip segments. (B) Transition from keratotic dysplasia to nonkeratotic area. (C) Mild dysplasia with basal cell hyperplasia and festooned rete ridges. (D) p53 is strongly positive within nuclei in a continuous band within the basal and suprabasal cells of the majority of rete ridges. (E) p53 is minimally expressed in the normal-appearing skip segment.

    Fig. 11.14, (A) Hyperkeratosis with multiple skip segments. (B) Hyperkeratotic area exhibits moderate epithelial dysplasia. (C) Hyperkeratosis with skip segments associated with squamous cell carcinoma (right) . (D) Hyperkeratosis with moderate epithelial dysplasia sandwiches nonkeratinized skip segment exhibiting mild dysplasia.

  • Festooned, bulbous, or drop-shaped rete ridges ( Fig. 11.15 ).

    Fig. 11.15, Festooned and drop-shaped rete ridges in dysplasia. (A) Festooned rete ridges with basal cell hyperplasia: mild to focally moderate dysplasia. (B) Drop-shaped rete ridges with basal cell hyperplasia and nuclear crowding involving half the thickness of the epithelium: moderate dysplasia. The keratin thickness is greater than the thickness of the epithelium.

  • Bulky epithelial proliferation, especially if endophytic and without or with minimal leukocyte exocytosis or spongiosis ( Figs. 11.16 and 11.17 ); many of these are thick plaques or masses clinically.

    Fig. 11.16, Bulky epithelial proliferation and cytologic dysplasia (floor of mouth). (A) Bulky epithelial proliferation with a central area of cytologic dysplasia. (B) Bulky epithelial proliferation with minimal cytologic atypia, not reactive in nature. (C) Parakeratosis with moderate epithelial dysplasia.

    Fig. 11.17, Atypical bulky squamous proliferation with dysplasia. (A) Bulbous confluent rete ridges with slightly endophytic growth; note normal thickness of epithelium on left. (B) Dyscohesion and cells with increased nuclear:cytoplasmic ratio. (C) Basal cell hyperplasia where cells have increased nuclear-to-cytoplasmic ratio with an area of more differentiated squamous cells in the center.

TABLE 11.2
Histopathologic Features of Dysplasia
Architectural features (best seen at low power)

  • Verrucous or papillary epithelial proliferation

  • Sharply demarcated keratosis, usually multifocal with epithelial atrophy (always worrisome), or acanthosis

  • Hyperkeratosis with skip segments

  • Festooned, bulbous, or drop-shaped rete ridges

  • Bulky squamous proliferation usually endophytic but may be exophytic or both

Organizational features (best seen at intermediate power)

  • Dyscohesion a

  • Basal cell hyperplasia leading to loss of normal stratification and polarity

  • Crowding of basal cells

  • Mitoses (even if normal-appearing) beyond the suprabasal keratinocytes

  • Keratin pearls at tips of rete ridges

Cytologic features (those noted on exfoliative cytology and best seen at high power)

  • Basal cell hyperplasia

  • Increased nuclear: cytoplasmic ratio

  • Variation in cell shape and size

  • Variation in nuclear shape and size

  • Coarse chromatin and prominent and/or multiple nucleoli

  • Hyperchromasia

  • Abnormal mitotic figures

  • Dyskeratosis and/or keratin pearl formation including glassy appearance of cytoplasm

  • Multinucleate epithelial cells with increased nuclear: cytoplasmic ratio

a Dyscohesion is separation of epithelial cells unassociated with inflammation and as such is not spongiosis where cells show intercellular inflammation and edema.

Hyperkeratosis, not reactive

This diagnostic phrase is applied to hyperkeratotic lesions that show architectural features as noted earlier, but that exhibit equivocal cytologic features of dysplasia (see Figs. 11.11 and 11.12 ). The most common features are demarcated and corrugated hyperkeratosis with skip segments and epithelial atrophy. These lesions exhibit malignant transformation to invasive carcinoma in 5% of cases, similar to lesions of mild dysplasia. Fig. 11.18 provides a theoretical model for progression of hyperkeratotic lesions that are not reactive, to dysplasia to invasive carcinoma.

Fig. 11.18, Progression of hyperkeratosis, not reactive to dysplasia to invasive cancer based on a three-strike model of carcinogenesis.

Organizational evidence of dysplasia

These changes show the abnormal relationship of dysplastic cells to each other within the epithelium ( Table 11.2 ). Some of these findings are referred to as architectural features using the WHO nomenclature.

  • Dyscohesion (as opposed to spongiosis associated with intercellular edema and inflammatory cell transmigration) ( Fig. 11.19 ).

    Fig. 11.19, (A) Parakeratosis with dysplasia characterized by prominent dyscohesion and dyskeratosis, clearly evident on intermediate power (B) Dyscohesion with cells separated but still with intercellular bridges, and minimal inflammation. There are basal and parabasal cells with increased nuclear:cytoplasmic ratio and dyskeratosis.

  • Basal cell hyperplasia and crowding leading to loss of normal upward maturation often referred to as loss of normal stratification and polarization of the epithelium (see later).

  • High mitotic figures, normal or otherwise beyond the basal and immediate parabasal cell layers ( Fig. 11.20 A–B).

    Fig. 11.20, (A) Marked hyperkeratosis with the keratin thickness equal to the epithelium thickness focally on left. (B) There is mild epithelial dysplasia characterized by cells with increased nuclear:cytoplasmic ratio and high mitotic figures (arrows) . (C) Keratin pearl formation at the tip of the rete ridges surrounded by dysplastic epithelial cells.

  • Keratin pearl formation at the tips of rete ridges ( Fig. 11.20 C). It is rare to see this without other cytologic features of dysplasia.

Cytologic evidence of dysplasia

In many cases, lesions are a combination of mild-to-moderate or moderate-to-severe dysplasia especially within large lesions when more than one biopsy is taken.

  • Cytologic features are similar to those at other mucosal sites and are readily noted on exfoliative cytology (see Table 11.2 ); reactive epithelial atypia from inflammation may show the same features.

  • Mild dysplasia: less than one-third of the thickness of the epithelium is involved by dysplasia ( Fig. 11.21 ).

    Fig. 11.21, Mild epithelial dysplasia. (A) Hyperkeratosis and cells with increased nuclear:cytoplasmic ratio involve less than one-third of the epithelium. (B) Many candidal hyphae within the parakeratin in the absence of spongiotic pustules, spongiosis or leukocyte transmigration, basal cell hyperplasia, nuclear hyperchromasia, and pleomorphism involving only the lower few layers of epithelial cells. (C) Basal cell crowding and cells with increased nuclear:cytoplasmic ratio involving less than one-third of the epithelium; note bulbous rete ridges.

  • Moderate dysplasia: greater than one-third and less than two-thirds of the thickness of the epithelium is involved by dysplasia ( Figs. 11.22 and 11.23 ).

    Fig. 11.22, Mild-to-moderate dysplasia. (A) Parakeratosis with festooned and bulbous rete ridges. (B) Mild epithelial dysplasia within this rete ridge. (C) Moderate epithelial dysplasia within this adjacent rete ridge with basal cell hyperplasia involving half the thickness of the epithelium.

    Fig. 11.23, Moderate epithelial dysplasia. (A) Parakeratosis, dyscohesion, and festooned rete ridges. (B) Basal cell hyperplasia, suprabasal mitotic figures, and festooned rete ridges. Moderate epithelial dysplasia. (C) Parakeratosis, dyscohesion, cells with hyperchromatic and pleomorphic nuclei and dyskeratosis involving two-thirds of the epithelium. (D) Dyscohesion, basal cell hyperplasia, and pleomorphism involving greater than one-third of the epithelium.

  • Severe dysplasia: greater than two-thirds but less than the full thickness of the epithelium is involved by dysplasia ( Figs. 11.24 and 11.25 ).

    Fig. 11.24, Moderate-to-severe dysplasia. (A) Hyperkeratosis with dyscohesion and pleomorphic cells involving half to two-thirds of the epithelium for the most part. (B) Another area of the same lesion showing markedly pleomorphic and multinucleated dysplastic epithelial cells involving greater than two-thirds of the epithelium. The giant cells have little cytoplasm.

    Fig. 11.25, Severe dysplasia. (A) Moderate dysplasia is present on the right and severe dysplasia on the left . (B) Marked dyscohesion with pleomorphic and hyperchromatic cells and dyskeratosis.

  • Carcinoma-in-situ: full thickness involvement of the epithelium is involved by dysplasia ( Figs. 11.26 and 11.27 ).

    Fig. 11.26, (A) Carcinoma-in-situ on the left with full thickness involvement of the epithelium and severe dysplasia on the right where the superficial two to three layers of keratinocytes are mature and still horizontally aligned. (B) Cells have pleomorphic nuclei throughout the epithelium and there are many high mitotic figures.

    Fig. 11.27, Carcinoma-in-situ. (A) Parakeratosis, full thickness dysplasia with pale cells. (B) Pleomorphic cells with marked dyskeratosis. (C) Some cells have abundant, pale, glassy, slightly fibrillar cytoplasm, a form of dyskeratosis. (D and E) Full thickness dysplasia composed of pale keratinocytes that exhibit dyskeratosis and glassy cytoplasm.

  • p53 nuclear positivity is often present in a fairly continuous and multilayered band at the lower half of rete ridges in dysplastic cells (see Fig. 11.13 D–E). However, a null type staining (completely negative without wild-type immunoreactivity) has also been reported ( Fig. 11.28 A–B). Strong, continuous p53 positivity by immunohistochemistry correlates with TP53 mutational status. In some cases where it is difficult to be certain whether cytologic atypia is caused by inflammation, p53 immunostaining may be useful (see Fig. 11.28 C–D).

    Fig. 11.28, Severe epithelial dysplasia exhibiting null p53 status. (A) Thick parakeratosis and severe epithelial dysplasia with dyscohesion, dyskeratosis and pleomorphism; note lymphocytic band. (B) p53 is entirely negative without wild-type positivity. Inflamed epithelial dysplasia (C) Parakeratosis with acanthosis, epithelial atypia, and chronic inflammation. (D) Elongated rete ridges exhibit mild epithelial atypia, and p53 is present in a continuous pattern confirming the presence of dysplasia (inset) .

  • Low-grade dysplasia exhibits cells with fewer cytologic features of dysplasia while high-grade dysplasia exhibits cells with a larger number of cytologic features of dysplasia regardless of the thickness of the epithelium, although from a practical perspective, the thicker the epithelium, the more features of dysplasia will be seen.

  • Lichenoid interface epithelial changes together with an interface lymphocytic band are seen in approximately 30% of cases of dysplasia and carcinoma. Of these cases, 75% exhibit a lymphocytic band which represents a T-cell response to neoantigens within dysplastic keratinocytes, similar to tumor-infiltrating lymphocytes or lymphocytic host response seen around invasive carcinoma ( Fig. 11.29 ). Referring to this lymphocytic band as “lichenoid” is confusing and should be avoided because it may cause the clinician to erroneously assume that the dysplasia arose within lichen planus. Basal cell destruction and colloid body formation represent in 30% each of lichenoid features.

    Fig. 11.29, (A) Demarcated leukoplakia of the floor of mouth without reticulations. (B) Hyperkeratosis with a lymphocytic band at the interface. (C) Very mild epithelial atypia, qualifying for dysplasia given the clinical findings. The clinical lesion does not represent plaque-type lichen planus most of which likely represent leukoplakia that showed “lichenoid mucositis”.

  • Involvement of ducts by dysplasia must be documented, because deep margins may not be free of dysplasia if deep portions of duct are involved; this feature is associated with an increased rate of local recurrence as expected ( Figs. 11.30 ).

    Fig. 11.30, Moderate-to-severe epithelial dysplasia involving excretory duct. (A) Hyperkeratosis with dysplasia involving upper portion of the duct. (B) Moderate-to-severe epithelial dysplasia involving excretory duct. (C) The overlying epithelium exhibits dyscohesion and basal cell hyperplasia; the left duct is involved by dysplasia. (D) Pleomorphic and dysplastic cells involve the full thickness of the duct.

  • Moderate and severe epithelial dysplasia is more often associated with aneuploid lesions and strongly predictive of development of invasive carcinoma.

  • Actinic keratosis is fairly common on the lip vermilion and clinically consists of a discrete scaly papule that arises within actinic cheilitis , a diffuse or patchy atrophy and erythema of the vermilion, and blurring of the vermilion–skin interface ( Fig. 11.31 A). Actinic keratosis shows parakeratosis usually and conventional evidence of dysplasia while cases of hypertrophic actinic keratoses also form long rete ridges often in a radiating pattern (see Fig. 11.31 B–C).

    Fig. 11.31, (A) Actinic keratosis of the lower vermilion in the setting of (actinic cheilitis) diffuse chronic sun damage. (B) Parakeratosis with epithelial atrophy and vascular ectasia. (C) Mild-to-moderate epithelial dysplasia present. (D) Acantholytic dysplasia within hypertrophic actinic keratosis; p53 highlights the radiating elongated rete ridges (inset) . (E) Dysplastic and acantholytic keratinocytes.

  • Oral lichenoid lesion is a term that has come into popular use and now classified as a potentially malignant lesion by the WHO, although it is a poorly defined entity. It is used as a clinical term to mean a red and white lesion that is not clearly striated, which could represent an erythroleukoplakia, a known precancerous lesion. It is also used as a histopathologic term when lichenoid interface features are present whether dysplasia is present or not. To reduce confusion, the term lichenoid mucositis or lichenoid inflammation should be used in histopathology only to refer to reactive lesions since such interface changes are seen in 30% of dysplasias and carcinomas.

Differential diagnosis

  • Reactive epithelial atypia is sometimes difficult to differentiate from true dysplasia, especially in the presence of reepithelialization and healing ulceration; if one cannot be sure, using the phrases likely reactive or unsure if reactive helps in patient management. Correlating the histopathology with the appearance of the lesions is always helpful and is often essential for accurate diagnosis.

  • Lichen planus or lichenoid mucositis with reactive atypia tends to show destruction of basal cells (instead of basal cell hyperplasia) and colloid body formation; multinucleate epithelial cells with finely dispersed chromatin and abundant cytoplasm are often seen in reactive lesions while dysplastic multinucleated epithelial cells have little cytoplasm ( Fig. 11.32 ). Rebiopsy of any residual lesion after a few weeks treatment with an antiinflammatory medication is an important aspect of treatment of such cases exhibiting epithelial atypia with a strong inflammatory component.

    Fig. 11.32, Lichenoid mucositis with reactive epithelial atypia. (A) Hyperkeratosis and lymphocytic band at the interface. (B) Degenerated basal cells, colloid bodies, and reactive epithelial atypia with multinucleate epithelial cells with abundant cytoplasm. (C) Squamous cells exhibit reactive atypia abutting the typical subbasal cleft.

  • Lesions of primary candidiasis may show significant reactive atypia and in general will also exhibit acanthosis, spongiotic pustules, spongiosis and leukocyte transmigration; however, dysplastic epithelium is often colonized by Candida , but because of local immune dysregulation, these dysplastic changes are still present after antifungal therapy. As such, rebiopsy after antifungal therapy of any residual lesion is an important aspect of management.

Management and prognosis

  • Multiple biopsies should be performed for nonhomogeneous leukoplakia and proliferative leukoplakia. The use of adjunctive measures such as toluidine blue, autofluorescence, chemiluminescence, narrow band imaging, and other imaging modalities may be helpful in visualizing lesions and their margins.

  • Management of mild-to-moderate dysplasia is usually in the form of excision or careful follow-up depending on the clinical situation such as high-risk site, recurrence of leukoplakia from a site of carcinoma excision, poor health, age, size, and accessibility of lesion to name a few. In general, severe dysplasia and carcinoma-in-situ are treated with excision.

  • Laser excision exhibits the same rate of recurrence as scalpel excision.

  • Photodynamic therapy has been shown to result in complete remission in 76% of cases.

  • Topical 5-fluorouracil and imiquimod are effective for lip vermilion lesions and may be useful even in intraoral lesions.

  • Recurrence after removal or progression of residual disease after incomplete removal occurs in up to 30% of cases and risk factors include large lesional size, involvement of margins, and poor accessibility for complete removal of the lesion. Lesions on the gingiva and posterior tongue/floor of mouth are particularly prone to such recurrence almost always because of poor accessibility and incomplete removal.

  • The rate of malignant transformation to invasive cancer is higher in leukoplakias that are >4 cm, and in cases exhibiting moderate-to-severe or high-grade dysplasia versus mild dysplasia and is 1% to 2% per year. The overall rate of malignant transformation is 10% to 18% for localized conventional leukoplakia and 50% to 100% for proliferative leukoplakia depending on the length of follow-up.

  • Hyperkeratotic lesions that are not reactive and that exhibit architectural abnormalities should be carefully followed or excised/ablated if clinically appropriate.

  • Patients should receive lifetime follow-up not just because of recurrence but also because field cancerization places the patient at high risk for another primary site of dysplasia in the mouth.

References

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  • Alaizari NA, Sperandio M, Odell EW, Peruzzo D, Al-Maweri SA. Meta-analysis of the predictive value of DNA aneuploidy in malignant transformation of oral potentially malignant disorders. J Oral Pathol Med . 2018;47:97-103.

  • Bagan J, Scully C, Jimenez Y, Martorell M. Proliferative verrucous leukoplakia: a concise update. Oral Dis . 2010;16:328-332.

  • Brouns E, Baart J, Karagozoglu K, et al. Malignant transformation of oral leukoplakia in a well-defined cohort of 144 patients. Oral Dis . 2014;20:e19-e24.

  • Daley TD, Lovas JG, Peters E, et al. Salivary gland duct involvement in oral epithelial dysplasia and squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 1996;81:186-192.

  • Farah CS. Narrow Band Imaging-guided resection of oral cavity cancer decreases local recurrence and increases survival. Oral Dis . 2018; 24:89-97.

  • Giovannacci I, Vescovi P, Manfredi M, Meleti M. Non-invasive visual tools for diagnosis of oral cancer and dysplasia: a systematic review. Med Oral Patol Oral Cir Bucal . 2016;21:e305-e315.

  • Hanna GJ, Villa A, Mistry N, et al. Comprehensive immunoprofiling of high-risk oral proliferative and localized leukoplakia. Cancer Res Commun . 2021;1(1):30-40.

  • Iocca O, Sollecito TP, Alawi F, et al. Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck . 2020;42: 539-555.

  • Kresty LA, Mallery SR, Knobloch TJ, et al. Alterations of p16(INK4a) and p14(ARF) in patients with severe oral epithelial dysplasia. Cancer Res . 2002;62:5295-5300.

  • Kujan O, Oliver RJ, Khattab A, et al. Evaluation of a new binary system of grading oral epithelial dysplasia for prediction of malignant transformation. Oral Oncol . 2006;42:987-993.

  • Li CC, Almazrooa S, Carvo I, Salcines A, Woo SB. Architectural alterations in oral epithelial dysplasia are similar in unifocal and proliferative leukoplakia. Head Neck Pathol . 2021;15:443-460.

  • Li Y, Wang B, Zheng S, He Y. Photodynamic therapy in the treatment of oral leukoplakia: a systematic review. Photodiagnosis Photodyn Ther . 2019;25:17-22.

  • Lingen MW, Tampi MP, Urquhart O, et al. Adjuncts for the evaluation of potentially malignant disorders in the oral cavity: diagnostic test accuracy systematic review and meta-analysis-a report of the American Dental Association. J Am Dent Assoc . 2017;148:797-813.e52.

  • Lingen MW, Abt E, Agrawal N, et al. Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: a report of the American Dental Association. J Am Dent Assoc . 2017;148:712-727.e10.

  • Liu W, Wang YF, Zhou HW, et al. Malignant transformation of oral leukoplakia: a retrospective cohort study of 218 Chinese patients. BMC Cancer . 2010;10:685.

  • Odell E, Kujan O, Warnakulasuriya S, Sloan P. Oral epithelial dysplasia: recognition, grading and clinical significance. Oral Dis . 2021;27:1947-1976.

  • Mogedas-Vegara A, Hueto-Madrid JA, Chimenos-Kustner E, Bescos-Atin C. Oral leukoplakia treatment with the carbon dioxide laser: a systematic review of the literature. J Craniomaxillofac Surg . 2016;44:331-336.

  • Okoturo EM, Risk JM, Schache AG, Shaw RJ, Boyd MT. Molecular pathogenesis of proliferative verrucous leukoplakia: a systematic review. Br J Oral Maxillofac Surg . 2018;56:780-785.

  • Reichart PA, Philipsen HP. Oral erythroplakia—a review. Oral Oncol . 2005;41:551-561.

  • Sawada K, Momose S, Kawano R, et al. Immunohistochemical staining patterns of p53 predict the mutational status of TP53 in oral epithelial dysplasia. Mod Pathol . 2021;35:177-185.

  • Sathasivam HP, Nayar D, Sloan P, Thomson PJ, Odell EW, Robinson M. Dysplasia and DNA ploidy to prognosticate clinical outcome in oral potentially malignant disorders. J Oral Pathol Med . 2021;50:200-209.

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Human papillomavirus (HPV)–associated oral epithelial dysplasia

This condition has a strong male predilection, similar to nasopharyngeal and tonsillar HPV-associated carcinoma. Although the precursor dysplastic lesion is difficult to identify in tonsillar carcinoma, likely because of the convoluted nature of the crypt epithelium, this HPV-driven oral condition presents as a leukoplakia and is easily identified by simple inspection of the oral mucosa. Older cases with similar histopathology have been referred to as “koilocytic dysplasia.”

Clinical findings

  • This occurs most frequently in the seventh decade with a 5–6:1 male predilection; it is indistinguishable from other leukoplakias and presents as a well-demarcated white plaque, sometimes verrucous, usually on the ventral tongue and floor of mouth ( Fig. 11.33 ).

    Fig. 11.33, (A) Human papillomavirus (HPV)–associated dysplastic leukoplakia on the left ventral tongue. (B) HPV-associated carcinoma on the ventral tongue.

Etiopathogenesis and histopathologic features

This particular type of oral epithelial dysplasia is associated with high-risk HPV types (mostly type 16), and it shares some features with Bowen disease. Transcriptionally active HPV produces E6 and E7 oncoproteins that inactivate p53 and pRb tumor suppressor proteins, respectively, with the latter leading to overexpression of p16, a surrogate marker for such cancers.

  • There is bright compact parakeratosis, although hyperkeratosis may also be present, and papillary architecture is an infrequent finding. There is full thickness involvement of the epithelium by basaloid cells with high nuclear-to-cytoplasmic ratio as well as cells exhibiting HPV viral cytopathic effect. This is characterized by cells in varying stages of apoptosis from karyorrhectic cells (similar to mitosoid bodies seen in Heck disease) to degenerated cells with pyknotic nuclei, to apoptotic cells which are dyscohesive with surrounding halos; conventional koilocytes may be present ( Figs. 11.34 and 11.35 ).

    Fig. 11.34, Human papillomavirus (HPV)–associated oral dysplasia. (A) Parakeratosis and many large, atypical cells exhibiting pericellular halos. (B) Karyorrhectic and apoptotic cells; adjacent cells show nuclear atypia and dysmaturation. (C) DNA in situ hybridization is positive for high-risk HPV types; note abrupt transition to noninvolved epithelium that corresponds to clinical demarcation of lesion. (D) p16 positivity within most of the keratinocytes beneath the parakeratin in a pattern corresponding to the positive study for high-risk HPV in C.

    Fig. 11.35, HPV-associated oral dysplasia. (A) Hyperkeratosis and papillary epithelial proliferation. (B) Full thickness dysmaturation characterized by cells with increased nuclear:cytoplasmic ratio, many karyorrhectic cells with pericellular halos and brightly eosinophilic apoptotic cells. (C) Block positivity for p16 for all keratinocytes without staining of keratin layer. (D) RNA in situ hybridization shows dot positivity.

  • A continuous band of p16 positivity (block positivity) within the nuclei and cytoplasm of almost all keratinocytes is present (see Figs. 11.34 C and 11.35 C).

  • High-risk HPV types are identified in up to 80% of cases by in situ hybridization (see Figs. 11.34 D and 11.35 D), and most of these represent HPV-16.

Differential diagnosis

  • Heck disease also exhibits karyorrhectic cells (mitosoid bodies) but does not show significant atypia/dysplasia or p16 positivity.

  • Conventional epithelial dysplasia and carcinoma-in-situ does not show significant numbers of such apoptotic cells and is negative for p16 and high-risk HPV.

  • Bowenoid papulosis usually occurs on the genitalia, may rarely occur in the mouth, and presents as multiple papules clinically; bowenoid papulosis and Bowen disease of the skin are also associated with HPV-16 and may show p16 positivity but often not in a diffuse pattern, and often spares the basal cells.

Management and prognosis

  • Excision with clear margins is treatment of choice and 10% to 15% of cases develop squamous cell carcinoma.

References

  • Alsabbagh A, Robins TL, Harriman A, et al. Surrogate markers for high-risk human papillomavirus infection in oral epithelial dysplasia: a comparison of p16, Ki-67, and ProExC. Oral Surg Oral Med Oral Pathol Oral Radiol . 2020;129:246-259.e1.

  • Argyris PP, Wilkinson PE, Jarvis MC, et al. Endogenous APOBEC3B overexpression characterizes HPV-positive and HPV-negative oral epithelial dysplasias and head and neck cancers. Mod Pathol . 2021;34:280-290.

  • Harvey NT, Leecy T, Wood BA. Immunohistochemical staining for p16 is a useful adjunctive test in the diagnosis of Bowen’s disease. Pathology . 2013;45:402-407.

  • Kazlouskaya V, Shustef E, Allam SH, Lal K, Elston D. Expression of p16 protein in lesional and perilesional condyloma acuminata and bowenoid papulosis: clinical significance and diagnostic implications. J Am Acad Dermatol . 2013;69:444-449.

  • Khanal S, Shumway BS, Zahin M, et al. Viral DNA integration and methylation of human papillomavirus type 16 in high-grade oral epithelial dysplasia and head and neck squamous cell carcinoma. Oncotarget . 2018;9:30419-30433.

  • Lerman MA, Almazrooa S, Lindeman N, Hall D, Villa A, Woo SB. HPV-16 in a distinct subset of oral epithelial dysplasia. Mod Pathol . 2017;30:1646-1654.

  • McCord C, Xu J, Xu W, et al. Association of high-risk human papillomavirus infection with oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol . 2013;115:541-549.

  • Rinaggio J, Glick M, Lambert WC. Oral bowenoid papulosis in an HIV-positive male. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2006;101:328-332.

  • Woo SB, Cashman EC, Lerman MA. Human papillomavirus-associated oral intraepithelial neoplasia. Mod Pathol . 2013;26:1288-1297.

Submucous fibrosis

Submucous fibrosis is a premalignant condition seen in areca nut and betel leaf users, a practice common in India, parts of South East Asia, and Taiwan. It is highly associated with the development of dysplasia and invasive carcinoma.

Clinical findings

  • Patients report burning and increasing trismus, and there are diffuse, pale, marble-like, and keratotic areas on the buccal mucosa, soft palate, and tongue in patients who use areca nut products; late lesions have a taut fibrotic texture sometimes with a “piano wire” feel to the mucosa from fibrous bands, although fibrosis may also be diffuse; erythema and ulcers may be present. The teeth are characteristically stained reddish-brown and the appearance of a white plaque (leukoplakia) or red plaque (erythroplakia) usually precedes the development of squamous cell carcinoma ( Fig. 11.36 ).

    Fig. 11.36, Submucous fibrosis. (A) Poorly demarcated white and ulcerated (yellow) areas on the buccal mucosa with brown staining of the teeth from areca nut chewing. (B) Same patient as in A; marked fibrosis leading to an interincisal opening of only 20 mm (normal 40–45 mm in males). (C) Squamous cell carcinoma arising from the buccal mucosa and extending onto the lower lip mucosa in a patient with submucous fibrosis; note the red-brown staining of teeth from this habit.

  • Staging systems have been developed based on the clinical presence of erythema and ulcers, pallor of the mucosa, and depapillation of the tongue, presence of fibrous bands, degree of interincisal opening, and the presence of leukoplakia, erythroplakia, or squamous cell carcinoma.

Etiopathogenesis and histopathologic features

Areca nut contains abundant copper and flavonoids that act together to stabilize and enhance cross-linking of collagen resulting in fibrosis. Arecoline, a major areca nut alkaloid, stimulates collagen synthesis and reduces collagen degradation, likely through the transforming growth factor-β pathway mediated by αvβ6; these alkaloids can be converted to carcinogenic nitrosamines. Areca nut products are used in many parts of India, South East Asia, and the Pacific Islands each with its own constituents. The pan or pan masala consists of a Piper betle leaf, also referred to as betel leaf, wrapped around a ripe or unripe areca nut, slaked lime, spices, and other constituents such as sweetening agents and catechu, an astringent vegetable extract containing tannin derived from the Acacia catechu tree; tobacco is sometimes added. Gutka has a larger proportion of tobacco and is associated with more rapid development of oral lesions. Many of these products are now prepackaged for ease of use. Taiwanese and Chinese betel quids do not usually contain tobacco.

  • There is hyperkeratosis, epithelial atrophy, and diffuse fibrosis of varying severity in the lamina propria; the collagen becomes dense and hyalinized with prolonged use ( Fig. 11.37 ). Acanthosis is more often noted in patients using areca nut products with tobacco.

    Fig. 11.37, Submucous fibrosis. (A) Fibrosis of the lamina propria with mild chronic inflammation; epithelium has tapered rete ridges and does not exhibit dysplasia. (B) Moderately hyalinized collagen in the lamina propria and mild chronic inflammation.

  • Dysplasia and invasive squamous cell carcinoma develop in long-standing keratotic lesions with the same histopathologic features as conventional leukoplakia (see earlier) ( Fig. 11.38 ).

    Fig. 11.38, Submucous fibrosis with dysplasia. (A) The epithelium exhibits moderate dysplasia with basal cell hyperplasia, and marked fibrosis and stromal hyalinization in the lamina propria. (B) The epithelium exhibits basal cell hyperplasia, nuclear hyperchromasia, and bulbous rete ridges.

  • Lesions have been classified as early, intermediate, or advanced based on the presence of type I or type III collagen and elastic fibers. Early and intermediate lesions have type III collagen and elastin and these are lost in advanced lesions where type I collagen predominates.

Differential diagnosis

  • Progressive systemic sclerosis appears similar, but the presence of anticentromere and anti–Scl-70 antibodies and a negative history of areca nut use differentiate between the two.

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