Oral Oncology xxx (2008) xxxxxx

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Oral Oncology

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Potentially malignant disorders of the oral and oropharyngeal mucosa;terminology, classification and present concepts of management

Isac van der Waal *

VU University Medical Center (VUmc)/Academic Centre for Dentistry Amsterdam (ACTA), Department of Oral and Maxillofacial Surgery/Pathology,P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

a r t i c l e i n f oAvailable online xxxx

Keywords:Oral leukoplakiaOral lichen planusActinic cheilitisSubmucous fibrosisPotentially malignant oral disorders1368-8375/$ - see front matter 2008 Elsevier Ltd. Adoi:10.1016/j.oraloncology.2008.05.016

* Tel.: +31 20 444 4039; fax: +31 20 444 4046.E-mail address: i.vanderwaal@vumc.nl

Please cite this article in press as: van der(2008), doi:10.1016/j.oraloncology.2008.0s u m m a r y

In a recently held WHO workshop it has been recommended to abandon the distinction between poten-tially malignant lesions and potentially malignant conditions and to use the term potentially malignantdisorders instead. Of these disorders, leukoplakia and erythroplakia are the most common ones. Thesediagnoses are still defined by exclusion of other known white or red lesions. In spite of tremendous pro-gress in the field of molecular biology there is yet no single marker that reliably enables to predict malig-nant transformation in an individual patient. The general advice is to excise or laser any oral oforopharyngeal leukoplakia/erythroplakia, if feasible, irrespective of the presence or absence of dysplasia.Nevertheless, it is actually unknown whether such removal truly prevents the possible development of asquamous cell carcinoma.At present, oral lichen planus seems to be accepted in the literature as being a potentially malignant dis-order, although the risk of malignant transformation is lower than in leukoplakia. There are no means toprevent such event. The efficacy of follow-up of oral lichen planus is questionable. Finally, brief attentionhas been paid to oral submucous fibrosis, actinic cheilitis, some inherited cancer syndromes and immu-nodeficiency in relation to cancer predisposition.

2008 Elsevier Ltd. All rights reserved.Introduction

In a World Health Organization (WHO) Workshop, held in 2005,the terminology, definitions and classification of oral lesions with apredisposition to malignant transformation have been discussed.The term potentially malignant was preferred above premalig-nant or precancerous;1 furthermore, it has been recommendedto abandon the traditional distinction between potentially malig-nant lesions and potentially malignant conditions and to use theterm potentially malignant disorders instead.

In this treatise, attention will be mainly paid to leukoplakia anderythroplakia. Furthermore, lichen planus and submucous fibrosiswill be discussed, as well as a number of miscellaneous potentiallymalignant disorders.

Leukoplakia

Definition and terminology

Leukoplakia is at present defined as A white plaque of ques-tionable risk having excluded (other) known diseases or disordersll rights reserved.

Waal I, Potentially maligna5.016that carry no increased risk for cancer.1 Examples of whiteor predominantly white diseases of the oral mucosa thatcarry no increased risk for cancer development are shown inTable 1.

The term leukoplakia can be used at different levels of certainty(C-factor) as a clinical term only (C1 or C2) or as a clinicopatholog-ical term (C3 or C4), as shown in Table 2.

Epidemiology and etiology

The estimated reported prevalence of oral leukoplakia, world-wide, is approximately 2%.2 However, when viewed in relation toan annual malignant transformation rate of 1%, this prevalence fig-ure would result in development of oral cancer in 20 per 100,000populations per year. Obviously, this cancer incidence figure, basedon malignant transformation of oral leukoplakia alone is much toohigh. Probably, the prevalence of oral leukoplakia has to be set at amore realistic figure of less than 0.5%. There are some geographicaldifferences with regard to the gender distribution.

Leukoplakia is six times more common among smokers thanamong non-smokers.3 Alcohol is an independent risk factor,regardless of beverage type or drinking pattern.4 There are conflict-ing results of studies related to the possible role of human papillo-mavirus infection.57nt disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol

mailto:i.vanderwaal@vumc.nlhttp://www.sciencedirect.com/science/journal/13688375http://http://intl.elsevierhealth.com/journals/oron/

Table 1The most common white or predominantly white benign diseases of the oral mucosaand their main diagnostic criteria

Lesion Main diagnostic criteria

Aspirin burn History of local application of aspirin tabletsCandidiasis, pseudomembranous Clinical aspect (pseudomembranes, often

symmetrical pattern)

Candidiasis, hyperplastica

Frictional lesion Presence of mechanical irritation (e.g. habitof vigorous toothbrushing)

Hairy leukoplakia Clinical aspect (incl. bilateral localization onthe tongue); histopathology (incl. EBV)

Leukoedema Clinical aspect (incl. symmetrical pattern)Linea alba Clinical aspect (incl. location on the line of

occlusion in the cheek mucosa)Lupus erythematosus History of skin lesions; clinical appearance

(incl. bilateral pattern); histopathologyMorsicatio (habitual chewing or

biting of the cheek, tongue, lips)History of habitual chewing or biting;clinical aspects

Papilloma and allied lesions Clinical aspect; histopathologySyphilis, secondary (mucous

patches)Clinical aspect; demonstration of T.pallidum; serology

Tobacco-induced lesionsb

Smokers palate (nicotinicstomatitis)

Clinical aspect; history of smoking

Snuff induced lesion Clinical aspect; site were snuff is placedWhite sponge nevus Family history; clinical aspect (often

symmetrical pattern)

a There is no consensus in the literature as whether to recognize a hyperplasticsubtype of oral candidiasis: some prefer to refer to these lesions as Candida-asso-ciated leukoplakia.

b Palatal lesions in reverse smokers are considered potential malignant disorders.

Table 4Criteria used for diagnosing dysplasia11

ArchitectureIrregular epithelial stratificationLoss of polarity of basal cellsDrop-shaped rete ridgesIncreased number of mitotic figuresAbnormal superficial mitosesPremature keratinization in single cells (dyskeratosis)Keratin pearls within rete pegs

CytologyAbnormal variation in nuclear size (anisonucleosis)Abnormal variation in nuclear shape (nuclear pleomorphism)Abnormal variation in cell size (anisocytosis)Abnormal variation in cell shape (cellular pleomorphism)Increased nuclear-cytoplasmic ratioIncreased nuclear sizeAtypical mitotic figuresIncreased number and size of nucleoliHyperchromasia

Table 3Histopathological stages in epithelial precursor lesions11

1 Squamoushyperplasia

This may be in the spinous layer (acanthosis) and/or inthe basal/parabasal cell layers (basal cell hyperplasia);the architecture shows regular stratification withoutcellular atypia

2 Mild dysplasia The architectural disturbance is limited to the lowerthird of the epithelium accompanied by cytologicalatypia

3 Moderatedysplasia

The architectural disturbance extends into the middlethird of the epithelium; consideration of the degree ofcytological atypia may require upgrading

4 Severedysplasia

The architectural disturbance involves more than twothirds of the epithelium; architectural disturbance intothe middle third of the epithelium with sufficientcytologic atypia is upgraded from moderate to severedysplasia

5 Carcinomain situ

Full thickness or almost full thickness architecturaldisturbance in the viable cell layers accompanied bypronounced cytological atypia

Table 2Certainty (C)-factor of a diagnosis of oral leukoplakia

C1 Evidence from a single visit, applying inspection and palpation as the onlydiagnostic means (provisional clinical diagnosis)

C2 Evidence obtained by a negative result of elimination of suspected etiologicfactors, e.g. mechanical irritation, during a follow-up period of 24 weeks orin the absence of any suspected etiological factors (definitive clinicaldiagnosis)

C3 As C2, but complemented by incisional biopsy (provisional histopathologicaldiagnosis)

C4 Evidence following excision and pathological examination of the resectedspecimen (definitive histopathological diagnosis)

2 I. van der Waal /Oral Oncology xxx (2008) xxxxxx

ARTICLE IN PRESSClinical aspects

Leukoplakia may affect any site of the oral and oropharyngealcavity. Clinically, leukoplakia can be subdivided in a homogeneoustype (flat, thin, uniform white in colour) and a non-homogeneoustype. The non-homogeneous type has been defined as a white-and-red lesion (erythroleukoplakia), that may be either irregu-larly flat (speckled) or nodular. Verrucous leukoplakia is yet an-other type of non-homogeneous leukoplakia. Although verrucousleukoplakia usually has a uniform white appearance, its verrucoustexture is the distinguishing feature from homogeneous (flat) leu-koplakia. Verrucous leukoplakia is clinically indistinguishable fromthe clinical aspect of verrucous carcinoma. Proliferative verrucousleukoplakia (PVL) is a subtype of verrucous leukoplakia,8 beingcharacterized by multifocal presentation, resistance to treatmentand a high rate of malignant transformation.9,10 PVL seems moreprevalent among elderly women. There may or may not be a his-tory of tobacco use.

Histopathological aspects

Histopathologically, a distinction can be made between dys-plastic and non-dysplastic leukoplakia. The assessment and sever-Please cite this article in press as: van der Waal I, Potentially maligna(2008), doi:10.1016/j.oraloncology.2008.05.016ity of dysplasia is based on architectural disturbance accompaniedby cytological atypia. The WHO 2005 classification recognizes fivehistopathological stages in epithelial precursor lesions (Table 3).11

The criteria used for diagnosing dysplasia are shown in Table 4. Itshould be emphasized that dysplasia is a spectrum and that no cri-teria exist to precisely divide this spectrum into mild, moderateand severe categories. Furthermore, there may be a substantialinterobserver and intraobserver variation in the histopathologicalassessment of the presence and severity of epithelial dyspla-sia.1214 Perhaps a better consensus can be reached by modifyingthe WHO five tier system into a binary one, recognizing low-riskversus high-risk lesions.15 It has been suggested that an AgNORcut-point may be helpful to distinguish mild and moderate dyspla-sia.16 In Table 5 two other grading systems the Squamous Intra-epithelial Neoplasia (SIN) system and the Ljubljana classification ofSquamous Intraepithelial Lesions (SIL) are shown. Occasionally,koilocytic changes in dysplastic lesions (koilocytic dysplasia)can be observed, apparently related to the presence of intermedi-ate and high-risk human papillomavirus; the clinical significanceand potential for malignant transformation is as yet unclear.7 Yetanother subtype of dysplasia is lichenoid dysplasia (see discus-sion on lichen planus).

Occasionally, a diagnosis of verrucous carcinoma, carcinomain situ or invasive squamous cell carcinoma is made in the clinicalpresentation of leukoplakia; in such event the histopathologicaldiagnosis replaces the clinical diagnosis of leukoplakia. It is wellnt disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol

Table 5Classification schemes that histologically categorize precursor and related lesionsWHO 2005)11

WHOclassification

Squamousintraepithelial neoplasia(SIN)

Ljubljana classification squamousintraepithelial lesions (SIN)

Squamous cellhyperplasia

Squamous cell (simple) hyperplasia

Mild dysplasia SIN 1 Basal/parabasal cell hyperplasiaa

Moderatedysplasia

SIN 2 Atypical hyperplasiab

Severedysplasia

SIN 3c Atypical hyperplasiab

Carcinomain situ

SIN 3c Carcinoma in situ

a Basal/parabasal cell hyperplasia may histologically resemble mild dysplasia, butthe former is conceptually a benign lesion and the latter the lower grade of pre-cursor lesions.

b Risky epithelium. The analogy to moderate and severe dysplasia isapproximate.

c The advocates of SIN combine severe dysplasia and carcinoma in situ.

I. van der Waal /Oral Oncology xxx (2008) xxxxxx 3

ARTICLE IN PRESSrecognized, that (proliferative) verrucous leukoplakia may show aspectrum of histopathological changes, ranging from hyperkerato-sis with or without dysplasia to verrucous hyperplasia and verru-cous carcinoma. Some authors consider verrucous hyperplasia anearly stage of verrucous carcinoma,17 while others do make a dis-tinction between verrucous hyperplasia and verrucouscarcinoma.18

Malignant transformation

In a study from India, an annual malignant transformation rateof 0.3% have been reported.19 In studies from Western countriessomewhat higher figures have been mentioned; an annual malig-nant transformation rate of approximately 1% is probably a reason-able average figure for all types of leukoplakia together. It is wellappreciated that this figure is much higher for non-homogeneoustypes,20 including proliferative verrucous leukoplakia. The latterprobably nearly always transforms into verrucous carcinoma orsquamous cell carcinoma and may do so in a protracted courseof over 1015 years. Malignancies may develop within the site ofpre-existing leukoplakia, but may also occur elsewhere in the oralcavity or the upper aerodigestive tract.

The commonly recognized factors that statistically carry an in-creased risk of malignant transformation into a squamous cell car-cinoma are listed in Table 6. Of these risk factors, the presence ofepithelial dysplasia often correlating with a clinical non-homoge-neous, erythroleukoplakic subtype is in general regarded themost important indicator of malignant potential. Nevertheless, itshould be recognized that some dysplastic lesions may remainclinically unchanged or may even show complete regression.19 Fur-thermore, carcinomatous transformation may also take place innon-dysplastic leukoplakia.20 In fact, genetic changes, particularlyat chromosomes 3, have been demonstrated in the majority of ker-atotic, non-dysplastic lesions.21Table 6Reported risk factors of statistical significance for malignant transformation ofleukoplakia, listed in an at random order (not applicable in the individual patient)

Female gender Long duration of leukoplakia Leukoplakia in non-smokers (idiopathic leukoplakia) Location on the tongue and/or floor of the mouth Size > 200 mm2 Non-homogeneous type Presence of C. albican Presence of epithelial dysplasia

Please cite this article in press as: van der Waal I, Potentially maligna(2008), doi:10.1016/j.oraloncology.2008.05.016Although the presence of Candida albicans has been mentionedas a risk factor,22 it is remarkable that this microorganism seems tobe particularly present in leukoplakias at the commissures of themouth and at the dorsum of the tongue, while these sites are rarelyinvolved in cancer development. In several studies from the Wes-tern world, the borders of the tongue and the floor of the mouthhave been mentioned as high-risk sites, while this is not the casein India.19 In a study from Denmark also size was shown to be ofimportance, particularly when exceeding 200 mm2.20

In spite of tremendous progress in the field of molecular biol-ogy, there is as yet no single marker or set of markers that reliablyenables to predict malignant transformation of leukoplakia in anindividual patient with leukoplakia,11,23 perhaps with the excep-tion of expression of podoplanin24 suprabasal expression ofp53,25 angiogenesis,26 the presence of high-risk HPV types, suchas HPV 16,27 the immunohistochemically expression patterns ofcyclin D1, p27 and p63,28 or the expression of cytokeratin 8.29

The use of non-invasive genetic tests, using exfoliated or brushedcells of lesional tissue,3032 or molecular markers from saliva33,34

may prove to be a step forward in the search for relevant prognos-tic markers.

Management

A flowchart for the management of leukoplakia has been pre-sented in Table 7. In the presence of possible etiological factors,including tobacco habits,35 an observation period of not more thana somewhat arbitrarily chosen 24 weeks seems acceptable to ob-serve a possible regression after elimination of such factors. Ofcourse, it is well appreciated that complete regression may takemuch more time. On the other hand, one would not like to post-pone a biopsy for a too long time in case a biopsy has not been ta-ken already at the first visit. In patients with multifocal orwidespread leukoplakia multiple biopsies (field mapping), ifneeded using general anesthesia, should be considered.36 Particu-larly in case of a non-homogeneous leukoplakia an incisionalbiopsy may not be representative.37,38 In small leukoplakias, e.g.

Table 7Management of leukoplakia

LEUKOPLAKIA (Provisional clinical diagnosis C1*)

Elimination of possible cause(s), including tobacco habits No possible cause(s) (2-4 weeks to observe the result) (Definitive clinical diagnosis: C2)

Good response No response Biopsy (Definitive clinical diagnosis C2)

Histopathologically proven diagnosis (By exclusion of "other known lesions": C3 or C4)

Known lesion Non-dysplastic leukoplakia Dysplastic leukoplakia Known lesion Management accordingly Management accordingly

Treatment (if feasible, e.g. < 2-3 cm) Treatment (if feasible, e.g. < 2-3 cm) Follow-up in both treated Follow-up in both treated

and untreated patients and untreated patients at intervals of 6 months; lifelong (?) at intervals of 3 months; lifelong (?)

* C = certainty factor

4 I. van der Waal /Oral Oncology xxx (2008) xxxxxx

ARTICLE IN PRESSinclude a margin of just a few millimetres, although it is conceiv-able and actually demonstrated that nuclear changes in the epithe-lium are present well beyond clinically visible leukoplakia. Thisphenomenon most likely explains the risk of local recurrence andthe development of new leukoplakias. Recurrence rates vary in var-ious papers from almost zero up to 30%.53,60,61 There are no scien-tific data available about the possible value of follow-up and theoptimal intervals after treatment of leukoplakia; nevertheless,some suggestions have been provided in Table 7.

Uniform reporting; classification and staging system

In order to promote uniform reporting, the use of a classificationand staging system is recommended in which the size and the his-topathological features are taken into account (Table 8). In addi-tion, gender, age at the time of diagnosis, any etiologic factors, ifidentified, and the oral or oropharyngeal subsite(s) should be re-corded. The system presented in Table 8 has been slightly modifiedfrom a previously reported proposal;62 it has not been validatedyet.

The recording of treatment results should be standardized asmuch as possible, including the length of the follow-up intervalsand the total length of follow-up. After surgical excision (includinglaser surgery or evaporation) recurrences are not uncommon.When the recurrence is at the site of the primary lesion, the termrecurrence seems justified, indeed, irrespective of the time spanbetween the excision and the recurrence. When the recurrencedevelops at a distinct different oral subsite, it seems appropriateto refer to such lesion as a new leukoplakia.

In case of non-surgical treatment or observation, the findingsshould be expressed as a percentage related to the original sizePlease cite this article in press as: van der Waal I, Potentially maligna(2008), doi:10.1016/j.oraloncology.2008.05.016of the leukoplakia as follows: no change (stable disease), partialregression (>50%), complete regression, and progressive disease(>25%).63 The most suitable criterium to measure such changesseems, indeed, to be the size of the leukoplakia and not so muchthe whiteness and/or the texture of the lesion (Table 9). In caseof monitoring the lesion by one or more biopsies during follow-up, the possible change in the histopathological findings could thenbe reflected in the staging system shown in Table 8.

Erythroplakia

Erythroplakia is defined as A fiery red patch that cannot becharacterized clinically or pathologically as any other definabledisease.64 The clinical appearance may be flat or even depressedwith a smooth or granular surface. In case of a mixture of redand white changes such lesion is usually categorized as non-homo-geneous leukoplakia (erythroleukoplakia). Tobacco and alcoholuse are considered important etiologic factors. The possible roleof C. albicans is at present still unclear.

Prevalence figures of erythroplakia are only available from stud-ies performed in South- and Southeast Asia and vary between0.02% and 0.83%.65 Erythroplakia mainly occurs in the middle agedand the elderly. There is no distinct gender preference. Any site ofthe oral and oropharyngeal cavity may become involved, usually ina solitary fashion. This solitary presentation is often helpful in clin-ically distinguishing erythroplakia from erosive lichen planus, lu-pus erythematosus and erythematous candidiasis, since theselesions occur almost always in a bilateral, more ore less symmetri-cal pattern.

Histopathologically, erythroplakia commonly shows at leastsome degree of dysplasia and often even carcinoma in situ ornt disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol

Table 9Reporting of treatment results of oral leukoplakia: a proposal63

Age at the time of first admission Gender Etiologic factors, if present Type of treatment

Surgical (incl. CO2)Non-surgicalChemo-preventionObservation only

Response rate (in case of non-surgical treatment or observation withouttreatment)

No response (stable disease)Partial response (>50% reduction in size, but not complete)Complete responseProgressive disease (>25% increase in size or the appearance of a newlesion)

RecurrenceLeukoplakia at the same subsite, irrespective of time interval

New primaryLeukoplakia at a distinctly different subsite

Malignant transformation Malignant event in the head-and-neck region, outside the oral cavity Malignant event outside the head-and-neck region Length of follow-up

Table 8Classification and staging system for oral leukoplakias (OL-system)

L (size of the leukoplakia)L1 Size of single or multiple leukoplakias together 4 cmLX Size not specified

P (pathology)P0 No epithelial dysplasia (includes no or perhaps mild

epithelial dysplasia)P1 Mild or moderate epithelial dysplasiaP2 Severe epithelial dysplasiaPx Absence or presence of epithelial dysplasia not specified

in the pathology report

OL-staging systemStage I L1P0Stage II L2P0Stage III L3P0 or L1L2P1Stage IV L3P1, any L P2

General rules of the OL-staging system1. If there is doubt concerning the correct L category to which a particular case

should be allotted, than the lower (i.e. less advanced) category should be cho-sen. This will also be reflected in the stage grouping.

2. In case of multiple biopsies of single leukoplakia or biopsies taken from multi-ple leukoplakias the highest pathological score of the various biopsies should beused.

3. For reporting purposes the oral subsite according to the ICD-DA should be men-tioned (World Health Organisation, International Classification of Diseases.Tenth Revision. Application to Dentistry and Stomatology, ICD-DA, Geneva,1992).

I. van der Waal /Oral Oncology xxx (2008) xxxxxx 5

ARTICLE IN PRESSinvasive carcinoma.66 Probably by far the majority of erythroplak-ias will undergo malignant transformation. There are not enoughdocumented series that would allow to calculate a reliable annualmalignant transformation rate.

In general, erythroplakia needs to be treated because of its high-risk of malignant transformation. Besides, most erythroplakias aresymptomatic. Surgery, either by cold knife or by laser, is the rec-ommended treatment modality. As for excision of leukoplakia, noguidelines are available with regard to the width of the surgicalmargins. There are no data from the literature about the recurrencerate after excision of erythroplakias.Please cite this article in press as: van der Waal I, Potentially maligna(2008), doi:10.1016/j.oraloncology.2008.05.016Lichen planus

There is an ongoing debate in the literature whether patientswith oral lichen planus (OLP) carry an increased risk of develop-ing a squamous cell carcinomas. Nevertheless, there is a tendencyto accept that there is.6770 The reported annual malignant trans-formation rate is usually well below 1%. Apparently, such eventmay occur in all clinical types of OLP.71 Unfortunately, the issueof malignant transformation in OLP is blurred by the often pres-ent lack of clinicopathologic correlation in the diagnosis.72,73 Fur-thermore, there is the somewhat confusing histopathologicalterm lichenoid dysplasia,74 probably mainly used in case of abandlike lymphocytic infiltrate underneath dysplastic epithelium.When one accepts that oral lichen planus may transform into asquamous cell carcinoma, then it is conceivable that in suchevent dysplastic changes may occur, justifying the use of theterm lichenoid dysplasia. However, based on personal experiencethere is rarely clinical evidence for pre-existing lichen planus incase of lichenoid dysplasia; this has also been confirmed byothers.75

There are no possibilities to truly prevent malignant transfor-mation of oral lichen planus. The efficacy of continuous follow-up of oral lichen planus patients is questionable,68 although suchfollow-up has been recommended by various authors.7679Oral submucous fibrosis

The occurrence of oral submucous fibrosis (OSF) is more or lessrestricted to Southeast Asia, although a number of cases have beenreported in other parts of the world, such as South Africa, Greeceand the United Kingdom. The disease is most likely caused bythe habit of chewing areca and betel quid or substitute.80

Clinically, OSF is characterized by a burning sensation, blanch-ing and stiffening of the oral mucosa and oropharynx, and trismus.In advanced stages vertical fibrous bands appear in the cheeks, fau-cial pillars, and encircle the lips. Through an as yet unknown pro-cess, fibrosis and hyalinization occur in the lamina propria, whichresults in atrophy of the overlying epithelium. The atrophic epithe-lium apparently predisposes to the development of a squamouscell carcinoma in the presence of carcinogens. In a long-term fol-low-up study the annual malignant transformation rate wasapproximately 0.5%.81Some miscellaneous potentially malignant disorders

Actinic cheilitis

Actinic cheilitis is a clinical term for an ulcerative, sometimescrust-forming lesion of the mucosa of part or entire vermilion bor-der of the lower lip. The histopathologic spectrum varies fromhyperkeratosis with or without epithelial dysplasia to early squa-mous cell carcinoma in the presence of basophilic changes in thelamina propria. There may be a marked inflammatory cell infiltratepresent. The disease mainly occurs in elderly men. There are noincidence figures available from the literature. Depending on theclinical signs and symptoms, and the result of a biopsy, treatmentusually consists of superficial surgical excision (lip shave) orCO2-laser evaporation.82 The advantage of surgical excision is theavailability of a specimen for histopathologic examination. IfCO2-laser is used, a pretreatment biopsy should be taken. Othertreatment modalities such as photodynamic therapy, seem lesseffective.83 There are no follow-studies of untreated actinic cheili-tis that would allow to present annual malignant transformationrates.nt disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol

6 I. van der Waal /Oral Oncology xxx (2008) xxxxxx

ARTICLE IN PRESSSome inherited cancer syndromes

In xeroderma pigmentosum and Fanconis anemia there is anincreased incidence of malignancies, including oral cancer. 84

Immunodeficiency

In immunodepressed patients, e.g. due to the prolonged use ofimmunosuppressive drugs after solid organ transplants, there isan increased risk of cancer, particularly of the lower lip.85 In pa-tients who underwent a liver transplant there was no increasedprevalence of oral or oropharyngeal cancer.86 There has been a re-port of an immunosuppressed liver transplant recipient in whomoral leukoplakia rapidly progressed to carcinoma.87

Particularly in the era before HAART therapy, but also more re-cently, a number of HIV-infected patients with oral cancer havebeen reported.88 Furthermore, oral cancer have been reported inpatients suffering from chronic Graft Versus Host Disease afterstem cell transplantation.89

Conflict of interest statement

None declared.

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Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of managementIntroductionLeukoplakiaDefinition and terminologyEpidemiology and etiologyClinical aspectsHistopathological aspectsMalignant transformationManagementUniform reporting; classification and staging system

ErythroplakiaLichen planusOral submucous fibrosisSome miscellaneous potentially malignant disordersActinic cheilitisSome inherited cancer syndromesImmunodeficiency

Conflict of interest statementReferences