Precursor Lesions for Squamous Carcinoma in the Upper Aerodigestive Tract

Erythroplakia, Leukoplakia, and Speckled Leukoplakia

Erythroplakia, leukoplakia, and speckled leukoplakia account for almost all lesions that transform and will be considered together first, as they share etiological and histological features, often coexist and have a shared evidence base.

Erythroplakia (Erythroplasia)

The term erythroplasia is adopted from the description of Queyrat in 1911 of an erythematous patch on the glans penis with a risk of malignant transformation.

Erythroplakia is a red, hyperemic patch on the oral mucosa ( Fig. 1.2 ). Some prefer the term erythroplasia to denote that these lesions are often diffuse poorly defined red areas with no distinct border, rather than a well-defined plaque. The combination of erythroplakia and leukoplakia is referred to as speckled leukoplakia or erythroleukoplakia . Though a speckled appearance indicates a high risk, red and keratotic lesions may often be found side by side and the combination is always sinister, even when the classical speckled pattern is not seen. Erythroplakia is typically depressed below the level of the surrounding mucosa.

Erythroplakia is a purely clinical term and has no histological use. It is defined it as a “fiery red patch that cannot be characterized clinically or pathologically as another definable lesion.” While the clinical identification of red mucosal changes in the oral cavity should raise the suspicion of dysplasia or carcinoma, some non-neoplastic conditions can cause similar appearances, including lichen planus, Candida albicans infection, and histoplasmosis. Erythroplakia is much less common than leukoplakia, resulting in remarkably fewer publications defining the term and establishing its associated etiologic, clinical, and pathologic features.

Most epidemiologic data concerning oral erythroplakia were collected in India and Southeast Asia, and indicate a prevalence of 0.02% to 0.83%, with the majority occurring in older individuals (sixth and seventh decades). In a study investigating the incidence of carcinoma in situ, which is the microscopic manifestation of many cases of oral erythroplakia, Bouquot and Ephros reported only six newly diagnosed cases per 1,000,000 persons each year, translating to 1500 cases diagnosed annually in the United States.

Erythroplakia is most commonly observed in thin mucosa and at high-risk sites for squamous carcinoma; the ventral tongue, floor of the mouth, anterior pillars of fauces, and retromolar trigone. Shafer and Waldron reported the most common site to be the floor of the mouth. In women, the combined mandibular alveolar mucosa, mandibular gingiva, and mandibular sulcus were most commonly affected. In men, this combined site was the least common site of occurrence. Erythroplakia does not usually affect the tongue but is frequent on the lateral tongue as a component of erythroleukoplakia. Bouquot and Ephros indicated that 50% of lesions diagnosed as oral erythroplakia measured less than 1 cm in greatest dimension, with the majority being less than 1.5 cm in diameter.

Erythroplakias carry the highest risk of malignant transformation of any OPMD. Most show severe dysplasia on biopsy and approximately half may harbor foci of squamous carcinoma on first biopsy. In several reports by Mashberg and colleagues, it was emphasized that “persistent asymptomatic erythroplakia rather than leukoplakia in high-risk sites of the oral cavity is the earliest and primary sign of oral carcinoma.”

Leukoplakia

The term leukoplakia, denoting white mucosal patches, was coined by Schwimmer, a Hungarian pathologist, in the second half of the 19th century. Currently, the WHO definition of leukoplakia is “a white plaque of questionable risk, having excluded (other) known diseases or disorders that carry no increased risk for cancer.” Over many years various definitions have been quoted, amended and often ignored. The history is reviewed in the current defining paper. However, those submitting biopsies may use the word either very loosely to mean any white patch, or to indicate that they consider a lesion to carry a risk of malignant transformation. Leukoplakia is not a histologic term, but the white appearance arises from increased keratinization, the thick keratin absorbing water and reflecting light ( Fig. 1.3 ).

The epidemiology of leukoplakia differs widely in different parts of the world and between studies, the latter partly caused by different criteria applied by examiners, their expertise, and the effort made to exclude insignificant keratosis. Most large epidemiological studies have not been able to exclude alternative diagnoses by biopsy. The overlapping and variable terminology makes drawing conclusions from these studies difficult. However, leukoplakia is relatively common and more frequent in populations with high incidence of smoking, and smokeless tobacco and alcohol use. The vast majority of leukoplakia detected in epidemiological studies is either not potentially malignant at all, or carries a very low risk. Conversely, high transformation rates may be reported in studies performed in secondary care.

Overall, the prevalence of oral leukoplakia varies between 0.6% and 10%, of which 0.2% to 1% has been reported to harbor dysplasia on histologic examination. The peak age of incidence is in the fifth to seventh decade. The peak age for dysplasia is the sixth decade, whereas that for carcinoma is a decade later, indirectly supporting the precursor role of dysplasia. Leukoplakia affects predominantly males, the reported percentages in males range from 54% ( n = 3256) to 78% ( n = 710).

Leukoplakias are most frequent on the buccal mucosa and maxillary and mandibular sulci, followed by the palate and lips, alveolar ridge, and dorsal tongue. However, white patches in these locations may result from friction, candidal infection and other causes and are less frequently associated with dysplasia. Conversely, leukoplakia affecting the ventral tongue, fauces, floor of mouth, or retromolar trigone is more likely to harbor dysplasia.

Speckled Leukoplakia (Erythroleukoplakia)

Terms, such as erythroleukoplakia, leukoerythroplakia, erosive leukoplakia, speckled leukoplakia, and speckled erythroplakia have been used to describe combined red and white oral mucosal changes ( Fig. 1.4 ). Current terminology considers these lesions to be a variant of leukoplakia rather than a specific entity, though, as noted earlier, it is the erythroplakic component that is the more significant, indicates the transformation risk and harbors the more severe dysplasia. The observation that many of the speckled leukoplakias may have previously been classified as leukoplakias may explain why some observers in the past found such a high frequency of malignant transformation in what was erroneously classified as “pure” or homogeneous leukoplakia.

Proliferative Verrucous Leukoplakia

Rather than a specific entity, proliferative verrucous leukoplakia (PVL) describes a clinico-pathological presentation of particularly high transformation risk. The term is somewhat of a misnomer, as lesions do not show proliferation as a prominent feature histologically, rather they enlarge and become multifocal in the mouth.

There are no absolute diagnostic features and the name has been used loosely in the literature, but it is important to restrict it to the correct patients, otherwise its significance is lost. Not all patients with multiple verrucous white lesions that develop carcinoma are cases of PVL. The key elements for diagnosis are an elderly patient, often female and with no conventional risk factors for carcinoma, with multiple leukoplakias that become more numerous and more widespread, more warty, verrucous, nodular or papillary, often over several decades ( Fig. 1.5 ). Development of erythematous areas is a late feature and may not occur.

Hansen and colleagues originally suggested 10 histologic stages in the continuum of PVL, which were reduced to 4 by Suarez and colleagues : clinical flat leukoplakia, verrucous hyperplasia, verrucous carcinoma, and conventional SCC. However, this is by no means a required progression and different lesions in one patient may display any of these appearances, and combinations of them, during their clinical course. Separate lesions do not progress synchronously.

The most common sites for the leukoplakias of PVL are the buccal mucosa (63%), gingiva (56%), and tongue (47%) in females, and the tongue (82%) and gingiva (45%) in males. The condition has been considered more prevalent in females (ratio of 4:1) by some, while others identify an equal gender distribution. Only 31% of patients have a history of tobacco use in some studies, while others prefer to exclude this diagnosis in smokers. The presence of HPV in PVL remains contentious, being mostly described using only polymerase chain reaction (PCR)-based methods. More stringent methods of HPV detection in PVL do not show any association with biologically significant (transcriptionally active) viral infection.

PVL often starts as a unifocal flat lesion, predominantly in mandibular or alveolar locations and buccal mucosa, which over many years develops a warty, somewhat papillary surface. Silverman and Gorsky studied 54 patients with PVL, 17 of whom were included in the original report by Hansen and colleagues. Seventy percent of patients developed carcinoma (mean, 7.7 years from initial diagnosis; range, 1–27 years); a second malignancy developed in another PVL site in 31.5% of the cases. In the final report by Hansen and colleagues, 87% of their patients developed SCC in a follow-up period that extended to 20 years in some patients. More than 40% of this cohort died of their carcinomas. If these data are combined with data from the Silverman and Gorsky series, the PVL-associated death rate is 50%.

It is often implied that malignant transformation is the defining characteristic and that PVL must be diagnosed retrospectively, but patients need to be identified earlier than the usual mean age of 62 years for aggressive treatment or close observation. Initial presentations of hyperkeratosis and homogeneous leukoplakia may not be recognized as PVL until the clinical course is recognized. Early lesions, and verrucous leukoplakias in general, often display minimal cytological atypia and may be mistakenly diagnosed as nondysplastic or mildly dysplastic, underestimating the risk. Many of the patients thought to have lichen planus with malignant transformation develop through a PVL-type progression, particularly those with gingival leukoplakia, and are probably cases of PVL with a more prominent than usual host response to their lesions. Only in later disease does dysplasia become evident.

PVL is considered to be resistant to treatment, and intervention remains contentious. The multifocality and a tendency to recur make all treatment options unreliable, including surgical excision, carbon dioxide (CO ₂ ) laser treatment, cryosurgery, chemotherapy, and photodynamic therapy and the morbidity from multiple excisions can be significant. Patients successfully treated for one carcinoma are at risk of further primary carcinomas, half developing a second and some patients several. In all cases, rigorous follow-up is required for PVL patients and the repeated biopsy of both old and new lesions to detect early invasion, with selective excision, remains the mainstay of treatment.

Verrucous Hyperplasia

Verrucous hyperplasia is a contentious diagnosis and one which we consider confusing and unhelpful. As noted in Table 1.1 and the section titled “Progression and Transformation of Oral Dysplastic Lesions,” the term hyperplasia has no place in the terminology of dysplasia or potential malignancy. Many verrucous leukoplakias display minimal cytological atypia, and so appear nondysplastic and histologically innocuous. However, the importance of architectural features of dysplasia is increasingly recognized and it is our preference to recognize a verrucous morphology in leukoplakia as an architectural feature of dysplasia and to automatically diagnose all such lesions as, at least, mildly dysplastic rather than hyperplastic. There is no site in the mouth, or UADT, that has a verrucous morphology physiologically and it never develops in response to physiological triggers, such as friction. Once a few lesions with a similar morphology are excluded, such as verruciform xanthoma, a verrucous architecture must be regarded with the utmost suspicion.

The concept of verrucous hyperplasia has a long history, and a variety of now-defunct diagnostic terms, including oral florid papillomatosis, have been considered equivalent in at least some cases. Verrucous hyperplasia was first described by Shear and Pindborg in 1980. It was said to involve the gingival and alveolar mucosa most frequently, followed, in decreasing order, by buccal mucosa, tongue, floor of the mouth, lip, and palate, similar to the distribution of PVL. However, in the initial report, 53% of patients had associated leukoplakia, 29% associated verrucous carcinoma, 66% epithelial dysplasia and in 10% a typical SCC. It seems obtuse to label such lesions as hyperplastic, when they appear to be transition zones at the margins of more dysplastic or neoplastic lesions. Verrucous hyperplasia has also been considered by some to be a phase in the development of PVL. Verrucous hyperplasia was said to be differentiated from verrucous carcinoma by the lack of the downward, pushing invasive growth exhibited by verrucous carcinoma. However, no criteria have been defined to distinguish verrucous hyperplasia from a verrucous leukoplakia with minimal cytological atypia and many now consider that verrucous hyperplasia is not a distinct entity.

In addition to the oral cavity, similar histological appearances have been described in the sinuses associated with inverted papillomas and in the larynx, but whether it is any more deserving of recognition as a separate entity at these sites is equally doubtful.

Oral Submucous Fibrosis and Changes in Betel Chewers

The diffuse submucous fibrosis of this condition is discussed in Chapter 4 . The current section covers only the mucosal changes seen both in submucous fibrosis and the mucosa of betel quid and areca users and their association with dysplasia.

The cause is chewing of betel quid or areca nut, consumed in various formats and with different ingredients in different parts of the world. The risk of carcinoma and dysplasia rise when tobacco is included in the quid, with higher frequency of chewing and when patients sleep with quid in place.

There are distinctive changes referred to as betel chewers’ mucosa that affect the site of habitual placement of the quid. Clinically, the mucosa is stained orange red, and this in vivo staining by dyes from the nut is visible in hematoxylin and eosin (H&E) sections as an orange discoloration of surface keratin. The surface of the epithelium is rough, peeling, and shredded, and may contain particles of impacted and trapped quid ( Fig. 1.6 ). These changes are considered a direct irritant reaction with superimposed trauma. These features alone do not constitute dysplasia and carry no risk of carcinoma but may be superimposed on dysplastic lesions.

Lichen planus-like clinical appearances develop in about 1% of users, and this has been misdiagnosed as lichen planus itself, but the close association with betel quid use suggests this is a combination of keratosis and erythema, accompanied by a lichenoid host response histologically. Clinically, the features are not typical of lichen planus, the keratosis is more variable, patchy, streaky rather than in well-defined striae and plaques, and the changes are most intense at the site of quid placement, often with atrophy or erythema and a radiating pattern of keratosis. As most patients have dark skin, melanin drop-out and clinical pigmentation are prominent and usually darker peripherally.

Histologically, there is a variable lichenoid host response with basal cell destruction and squamoid change, but often with an additional plasma cell element to the infiltrate. There is not usually a well-defined band of infiltrate. The infiltrate density varies but when dense and prominent within the epithelium, may mask dysplasia. Any lichenoid histological pattern in a betel quid user must be viewed with suspicion.

Users develop leukoplakia, erythroplakia and speckled leukoplakia that resemble those in nonusers, but the risk of carcinoma is extremely high, making this the most carcinogenic oral habit. Many studies on this topic are published. In one study from India where tobacco was included in the quid, the odds ratio for developing leukoplakia was 37.7 in females and 28 for those developing erythroplakia, rising to over 50 in long-term users. Transformation rates for leukoplakia and erythroplakia derived from Indian populations usually include topical tobacco or betel users. The features of dysplasia in users appear no different from those in nonusers. A zone of subepithelial fibrosis can be found at the site of betel quid placement and need not indicate submucous fibrosis, but the more extensive fibrosis of this disease can accompany all the changes noted earlier.

Lichen Planus

Despite decades of controversy, any premalignant potential of lichen planus remains contentious. There are good, fundamental reasons why a connection remains elusive. Firstly, lichen planus is not a specific entity but a terminal pathway of autoimmune destruction of keratinocytes that has multiple, and often unknown, causes and no individual specific diagnostic histological features. Secondly, if lichen planus does predispose to malignant transformation, the risk must be exceedingly small because lichen planus is so common. Certainly, it must be well below the 0.5% reported in hospital series. Third, the clinical diagnosis of lichen planus is also poorly defined, and overlaps with PVL and leukoplakia, especially when affecting the gingiva or in the plaque form. Finally, and probably most significant, dysplasia will often elicit a cell-mediated host response that closely mimics lichen planus histologically ( Fig. 1.7 ). A recent systematic review highlighted the difficulty in comparing data when diagnostic criteria are unclear or not stated and noted that lesions with mild degrees of dysplasia may well be diagnosed as lichen planus. The issue cannot be resolved on the basis of data published to date and, pending clarification, lichen planus remains classified by the WHO as an OPMD on the precautionary principle.

Molecular analysis has not proved helpful to resolve the issue. Allelic imbalance and loss of heterozygosity can be detected in apparently typical lichen planus, however significant genetic instability seems unlikely from first principles. Similarly, too high a proportion of lichen planus biopsies have been claimed to be aneuploid. Given the infrequency with which lichen planus becomes malignant, it would be expected to find genetic changes in only a minority of typical samples, if any.

Whether or not genuine lichen planus is an OPMD, dysplastic lesions often closely resemble lichen planus clinically. Many cases of PVL seem to be diagnosed as lichen planus in biopsies from the early stages of disease. A degree of dysplasia is incompatible with the histological diagnosis of lichen planus, and the diagnosis of carcinoma arising in lichen planus is often retrospective, rather than supported by good evidence of preexisting typical disease. Most of our institution’s cases of apparent carcinoma in lichen planus did not stand careful scrutiny and Van der Meij and colleagues considered that transforming “lichen planus” was always abnormal clinically to some degree.

The overlap in histological features between lichen planus and dysplasia with a host response makes confident diagnosis extremely difficult, indeed making this distinction may not even be possible in the early stages. Once dysplasia is present, making a diagnosis of lichen planus depends primarily on clinical features, detail of which is often not transmitted to the histopathologist. The destruction of basal cells in lichen planus induces a number of changes, including generalized early keratinization, large prickle cell nuclei with prominent eosinophilic nucleoli lying in the basal layer and, often, a proliferative response with reactive atypia in remaining basal cells ( Fig. 1.8 ). Features normally considered as atypia may be frequently found in lichen planus. However, there are no different ways of scoring dysplasia in the presence of a host response or in lichen planus and conventional criteria discussed later are applied. In borderline cases, or for additional reassurance, a diploid result on deoxyribonucleic acid (DNA) ploidy analysis appears helpful in excluding risk.

Discoid Lupus Erythematosus

Oral discoid lupus erythematosus has a resemblance to lichen planus clinically and histologically. Though accepted as an OPMD, the evidence is sparse and suffers the same diagnostic limitations as that linking lichen planus to carcinoma. However, the concept is supported by the fact that skin lesions may also undergo malignant transformation. There is a consensus that lupus erythematosus involving the vermilion border carries particular risk. While the evidence for intraoral carcinomas is largely in the form of case reports, some are convincing and have multiple primary carcinomas, and the risk of transformation seems to be accompanied by dysplasia of conventional appearance.

Human Papillomavirus and Oral Epithelial Dysplasia

Human papillomavirus was initially implicated as a causative agent in the development and progression of oral cavity carcinogenesis in the early 1980s. Since then, numerous studies have sought to detect the virus in precursor lesions of the oral cavity but have often used nonstandardized methods and investigated mixed series of lesions from diverse patient cohorts. Meta-analyses suggest that the pooled prevalence of high-risk HPV types in oral epithelial dysplasia is approximately 25%, and the odds ratio for detection of all genotypes is 3.9, using normal oral epithelium as the referent. However the overwhelming majority of these studies utilized PCR to detect HPV DNA, a technique known to have suboptimal specificity and overestimate viral prevalence. Furthermore, using PCR as a single modality test without longitudinal follow-up does not elucidate the biological relevance of the virus; HPV may be present as a transient bystander infection lacking any viral oncoprotein driver functions.

However, several groups have characterized a histomorphologically distinct group of lesions consistently harboring biologically active high-risk HPV. These have been called virus-associated dysplasia , oral Bowen’s disease , oral Bowenoid papulosis , koilocytic dysplasia , HPV-associated oral intraepithelial neoplasia , and HPV-associated oral epithelial dysplasia (HPV OED) , the last being the preferred term. This entity is defined by specific histomorphologic criteria in conjunction with the demonstration of high-risk HPV by in situ hybridization; the detection of viral DNA by PCR alone in oral dysplasia of conventional appearances is insufficient for diagnosis of HPV OED.

Pathologic Features and Differential Diagnosis

In the majority of cases, low magnification views show aberrant maturation and attenuation of the prickle zone with loss of stratification often involving half to full thickness of epithelial depth together with variable retention of a parakeratin layer. Initial reports included full thickness epithelial changes as a defining criterion (hence the term oral Bowenoid papulosis ), but more recent definitions allow these changes to be limited to the basal third. Interestingly, a single well-defined basal cell layer may be retained despite the presence of suprabasal atypia ( Fig. 1.9 ), a useful diagnostic feature likely reflecting the virus life cycle. Features that distinguish these lesions from conventional oral dysplasia are karyorrhexis and bizarre nuclear fragmentation ( Fig. 1.10 ) reminiscent of mitosoid bodies seen in multifocal epithelial hyperplasia (Heck’s disease), as well as isolated apoptotic or dyskeratotic cells, which may be present at any level but do not cluster ( Fig. 1.11 ). The isolated individual karyorrhectic, dyskeratotic and apoptotic cells, randomly distributed at any level of the epithelium, are characteristic and an indication for histological HPV testing, since these features are not usually seen in conventional oral epithelial dysplasia. Scattered pleomorphic or multinucleate cells may also be seen and, while not a consistent feature, koilocyte-like cells may be present in the superficial prickle zone ( Fig. 1.12 ). Though these features are highly characteristic, confirmation of biologically active HPV remains the absolute diagnostic criterion. Immunohistochemistry for p16 by itself cannot be used as a surrogate for HPV in dysplastic lesions, as discussed later.

There are currently no agreed grading systems in HPV OED, primarily since this entity is still relatively underrecognized. In their series, Woo and colleagues followed up cases of HPV OED for a median period of 8.5 months in 12 patients. Malignant transformation occurred in a single patient with “high-grade dysplasia” 25 months following initial biopsy. We have experience of a single case undergoing malignant transformation 9 years following an initial diagnosis of mild dysplasia. These reports are anecdotal and there is no large scale published data on the rate of malignant transformation in HPV OED. Until such knowledge becomes available, the clinical significance of individual and cumulative histological features of atypia remains unknown. HPV OED should therefore, at least for the present time, be graded and managed in the same way as conventional oral epithelial dysplasia. Therapeutic vaccination strategies remain untested in this disease.

Genetics

Little is known about the genetic changes in HPV OED, and mechanisms of HPV-associated oropharyngeal or cervical carcinogenesis cannot be assumed to be replicated in this disease. Nevertheless, a consistent observation is overexpression of the cell cycle regulatory protein p16, which accumulates as a result of the inactivation of the retinoblastoma tumor suppressor protein through the action of high-risk HPV E7 oncoprotein. Strong nuclear and cytoplasmic p16 overexpression co-localizes with morphological atypia, often with clear lateral demarcation from adjacent negatively stained epithelium ( Fig. 1.13 ). The pattern of p16 overexpression mimics that seen in varying grades of cervical intraepithelial neoplasia (CIN) and is usually strongest basally, corresponding to zones where early viral genes E6 and E7 are most transcriptionally active in the HPV life cycle. Conversely, the chromogenic signal of high-risk HPV DNA in situ hybridization may not overlap with areas of strongest p16 overexpression and is usually most pronounced in the superficial epithelium where viral copy number is greatest during replicative HPV infection ( Fig. 1.14 ). Some groups consider p16 overexpression as an appropriate surrogate marker for high-risk virus types in HPV OED, but it should be noted that there are no established cut-offs for p16 overexpression, since there are no agreed reference standards to test its accuracy. Furthermore, cyclin-dependent kinase ( CDK ) N2A , the gene that encodes for p16, is frequently deregulated as an early event in oral carcinogenesis. Therefore the utility of p16 is limited to providing evidence that any HPV present is biologically active. A combination of p16 and either HPV DNA in situ hybridization or HPV E6/7 RNA in situ hybridization is required.

Dyskeratosis Congenita

Dyskeratosis congenita is a rare disease characterized by nail dystrophy, reticular skin pigmentation, and oral leukoplakia that affects mainly males. It has numerous genetic forms and eponymous syndrome associations with slightly different clinical presentations and complications, but all are caused by defective telomerase activity.

Almost all cases develop oral leukoplakia toward the end of the first decade, usually on the buccal mucosa, tongue, and oropharynx. The plaques are initially cytologically bland with keratosis, acanthosis and no dysplasia, but develop dysplasia of conventional patterns as they progress clinically to a scarred and fissured appearance. Verrucous, atrophic and red areas appear later, with verrucous lesions being particularly common.

Fanconi Anemia

The defects in DNA repair in Fanconi anemia are a well-recognized predisposition to oral carcinoma, but there are few descriptions of precursor lesions. Bone marrow transplant is associated with graft-versus-host disease, which can produce oral white lesions resembling lichen planus and confusing the picture. Approximately 12% of young Fanconi anemia patients are reported to have leukoplakia. However, loss of heterozygosity can be detected both in lesions and in a wider field of apparently normal mucosa from a young age. The few reports suggest that erythroplakia and leukoplakia in Fanconi anemia patients show conventional patterns of dysplasia, but it seems clear that carcinoma in these patients is not necessarily associated with preexisting oral lesions.

Sideropenic Dysphagia

Sideropenic dysphagia (Patterson-Brown-Kelly or Plummer-Vinson syndrome), a condition characterized by iron deficiency anemia with frequent associated autoimmune diseases, affects the UADT with atrophy of the oral and pharyngeal mucosa and a predisposition to the development of multiple carcinomas, predominantly in the posterior oropharynx, but also in the mouth. This was a feared condition 50 years ago, but has declined to the extent that the existence of the condition is now questioned. Symptoms are those of severe anemia with dysphagia, mucosal atrophy and, usually, oral candidiasis and angular cheilitis. The presence of any preexisting lesion apart from atrophy is very poorly documented and there is no good information on histology, with most describing just atrophic epithelium.

Syphilis

Syphilis, previously in decline, is resurgent in both developed and developing countries, but the tertiary form associated with leukoplakia and oral carcinoma is now extremely rare. The combination of tertiary syphilis and leukoplakia carries a high risk of malignant transformation, well over 50%, regardless of treatment of the syphilis. The histological features of precursor lesions are rarely described but appear to show the features of conventional dysplasia.

Palatal Changes in Reverse Smokers

Reverse smoking, with the lighted end of a cigarette or cigar in the mouth, is practiced in many parts of the world for a variety of social, economic, and cultural reasons, often by women and children. Almost all reverse smokers use traditional coarse tobacco products rather than commercial cigarettes. The promoting effect of heat combined with tobacco carcinogens makes this a high-risk habit for carcinoma development, usually affecting the palate or dorsal tongue. Dysplasia and carcinoma are otherwise very rare at these sites and mild histological signs of dysplasia might be dismissed if the habit is not known.

Histological features of precursor lesions are subepithelial fibrosis, similar to submucous fibrosis, melanosis, and melanin drop-out with patterns of dysplasia, as seen in other tobacco-associated lesions.

Cheilitis Glandularis

Cheilitisglandularis (CG) is a poorly characterized condition first described by von Volkman in 1870. The condition is supposed to present with lip thickening, inflammation and clinically evident dilation of the minor gland ducts, from which thick mucin can be expressed. The lower lip is typically affected, but lesions on the upper lip have been reported. Because of the relatively nonspecific features, multiple causes have been suggested including tobacco use, bacterial infection, actinic radiation, and poor oral hygiene.

It has been claimed that the association with squamous cell carcinoma of the surface epithelium at the affected site is frequent, but a review of published cases reveals not only great heterogeneity in diagnosis but also that squamous carcinoma is relatively rare and associated with other recognized risk factors. The condition is clearly clinically distinctive, but its status as an OPMD is in question and may be explained by particular sensitivity to solar radiation.

Other Conditions

The junctional and dystrophic forms of epidermolysis bullosa predispose to oral carcinoma in young patients and the risk is considered high but there are no good clinical or histological descriptions of precursor lesions. Some variants of palmoplantar keratoderma (tylosis) are associated with a high risk of esophageal and oral carcinoma. Oral leukoplakia is usually present and shows conventional dysplasia.