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Historical perspective and nomenclature of potentially malignant or potentially premalignant oral epithelial lesions with emphasis on leukoplakia—some suggestions for modifications

  • Isaäc van der Waal
    Correspondence
    Reprint requests: Isaäc van der Waal, DDS, PhD, VU University Medical Center (VUmc)/Academic Centre for Dentistry Amsterdam (ACTA), Department of Oral and Maxillofacial Surgery and Oral Pathology, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
    Affiliations
    VU University Medical Center (VUmc)/Academic Centre for Dentistry Amsterdam (ACTA), Department of Oral and Maxillofacial Surgery and Oral Pathology, Amsterdam, The Netherlands
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Published:December 29, 2017DOI:https://doi.org/10.1016/j.oooo.2017.11.023
      Of the potentially (pre)maligant oral epithelial lesions, leukoplakia is the most common. A brief overview of the various definitions of leukoplakia that have been used in the past is presented here. A proposal has been made to modify the current definition. Clinically, for decades, leukoplakias have been divided into homogeneous and nonhomogeneous leukoplakias and further into different subtypes. A proposal has been made to slightly rearrange these subtypes. Furthermore, attention has been paid to a number of keratotic lesions that have been reported in the literature. It is expected that the increasing knowledge on carcinogenesis, including various genetic aspects, will be reflected in the definition of oral potentially (pre)malignant lesions in the near future.
      Statement of Clinical Relevance
      Oral leukoplakia is an important potentially (pre)malignant lesion. Proper use of the definition and terminology related to leukoplakia and leukoplakia-like lesions is of great importance for both clinical and research purposes.
      Of the potentially (pre)malignant oral epithelial lesions, leukoplakia, being a predominantly white lesion, is the most common one. The term leukoplakia was introduced in 1877 by Schwimmer, a Hungarian dermatologist.
      • Schwimmer E.
      Die idiopathischen Schleimhautplaques der Mundhöhle (Leukoplakia buccalis).
      Entirely red lesions, erythroplakias, are much less common than leukoplakias but carry a much higher risk of malignant transformation. The discussion on whether or not oral lichen planus is a potentially (pre)malignant disorder is ongoing. Therefore, this entity will not be discussed here.
      For a long time, the adjectives premalignant and precancerous have been used to designate an increased risk of malignant transformation of leukoplakias. A precancerous lesion has been defined as a morphologically altered tissue in which cancer is more likely to occur compared with its apparently normal counterpart, whereas a precancerous condition has been defined as a generalized state associated with a significantly increased risk of cancer.
      • World Health Organization
      Report from a Meeting on Investigators on the Histological Definition of Precancerous Lesions.
      However, no odds ratios that would define “more likely” and “significantly increased” have been provided by previous studies. Currently, preference is given to the term potentially (pre)malignant instead of the terms premalignant and precancerous. At present, this qualification is also used for fields of epithelial cells in the mucosa that are not visible clinically, harboring one or more cancer-associated genetic alterations, such as loss of 17 p (TP53) or 9 p (CDKN2 A encoding p16 Ink4 A).
      • Leemans C.R.
      • Braakhuis B.J.
      • Brakenhoff R.H.
      The molecular biology of head and neck cancer.
      Several attempts have been made in the past to provide a definition of leukoplakia, partly for scientific purposes and partly for use in the everyday practice. In 1968, Pindborg et al. defined oral leukoplakia as a white patch or plaque, not less than 5 mm in diameter, which could not be removed by rubbing and which could not be classified as any other diagnosable disease.
      • Pindborg J.J.
      • Renstrup G.
      • Jolst O.
      • Roed-Petersen B.
      Studies in oral leukoplakia: a preliminary report on the period prevalence of malignant transformation in leukoplakia based on a follow-up study of 248 patients.
      It was noted that the use of the term leukoplakia does not carry any histologic connotation. In 1978, the term was redefined by the World Health Organization (WHO) as a white patch or plaque that cannot be characterized clinically or pathologically as any other disease.
      • WHO Collaborating Centre for Oral Precancerous Lesions
      Definition of leukoplakia and related lesions: an aid to studies on oral precancer.
      The reasons for excluding the criteria of size and whether or not the lesion could be removed by rubbing have not been made explicit.
      At an international seminar held in 1983, the 1978 WHO definition of leukoplakia was slightly modified by the additional description that leukoplakia is not associated with any physical or chemical causative agent except the use of tobacco.
      • Axéll T.
      • Holmstrup P.
      • Kramer I.R.H.
      • Pindborg J.J.
      • Shear M.
      International seminar on oral leukoplakia and associated lesions related to tobacco habits.
      As a result, 2 types of leukoplakia were introduced: tobacco-associated leukoplakia and non–tobacco-associated (idiopathic or cryptogenic) leukoplakia. At yet another symposium, held in 1994, the 1978 WHO definition was left more or less unchanged.
      • Axéll T.
      • Pindborg J.J.
      • Smith C.J.
      • van der Waal I.
      Oral white lesions with special reference to precancerous and tobacco-related lesions: conclusions of an international symposium held in Sweden.
      However, a proposal was made to apply a provisional clinical diagnosis of leukoplakia in case of only a single oral examination and that a definitive diagnosis of leukoplakia should be based on the result of elimination of suspected etiologic factors, if any—and, in case of a persistent or an idiopathic lesion, as revealed on histopathologic examination.

      Present Definition and Classification of Oral Leukoplakia and Erythroplakia

      Definition

      In 2005, in another WHO-guided conference on the definition and terminology related to leukoplakia and leukoplakia-like (leukoplakic) lesions, the 1978 WHO definition was amended as follows: “The term leukoplakia should be used to recognize white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.”
      • Warnakulasuriya S.
      • Johnson N.W.
      • van der Waal I.
      Nomenclature and classification of potentially malignant disorders of the oral mucosa.
      It was added that leukoplakia is primarily a clinical term and has no specific histology. In Table I, a series of well-defined, known lesions or disorders that should be differentiated from leukoplakia is presented.
      Table IWell-defined predominantly white lesions or diseases that should be excluded from leukoplakia
      Lesion or diseaseMain diagnostic criteria
      Aspirin burn (including other types of chemical burns)History of prolonged application of aspirin tablets or other chemical agents.
      Candidiasis, hyperplasticSomewhat questionable entity; some refer to this lesion as candida-associated leukoplakia.
      Cinnamon-induced contact stomatitisIdentification of the frequent use of chewing gums and also of some toothpastes that contain a high concentrate of cinnamon; a biopsy may be helpful.
      Glassblower's white patchMainly located in the buccal mucosa; disappears within a few weeks after cessation of glassblowing.
      Hairy leukoplakiaUsually bilateral on the borders of the tongue; histopathology is important, including the immunohistochemical demonstration of the presence of Epstein-Barr virus.
      Keratotic lesions (include reversed smoking keratosis, sublingual keratosis, alveolar ridge keratosis, frictional keratosis, sanguinaria-associated keratosis, tobacco pouch keratosis, and keratosis of unknown significance)Different etiologies and various clinical presentations; in many cases, biopsy is indicated.

      Some of the keratotic lesions carry an increased risk of malignant transformation.
      Lesion caused by prolonged, direct contact of the oral mucosa with an amalgam restoration or other dental restorations; often listed as a lichenoid lesionDisappearance of the lesion within an arbitrarily chosen period of 2 to 4 weeks after removal of the restoration; pretreatment biopsy is recommended.
      LeukodemaClinical diagnosis of a veil-like aspect of the buccal mucosa, bilaterally; tends to disappear when stretched. Occurs almost exclusively in dark-skinned people.
      Lichen planus and lichenoid lesionOften a clinical diagnosis; occasionally difficult to distinguish from leukoplakia. A biopsy may be helpful.
      Linea albaClinical diagnosis; almost always bilateral on the line of occlusion.
      Lupus erythematosusOften a clinical diagnosis; almost always cutaneous involvement as well. Histopathology and direct immunofluorescence may be helpful.
      MorsicatioHistory of habitual chewing or biting. Clinical aspect of irregular whitish-yellowish flakes. Often bilateral.
      Papilloma and allied lesions (e.g., condyloma acuminatum, multifocal epithelial hyperplasia and verruca vulgaris)Clinical aspect; medical history. A biopsy, including human papillomavirus typing, may be helpful.
      Reversed smoking–induced palatal lesionMay mimic leukoplakia or erythroplakia; carries a high risk of malignant transformation.
      Skin graft (e.g., after vestibuloplasty)History of a previous graft.
      Smoker's palate (“stomatitis nicotina”)Usually a clinical diagnosis. Rarely becomes malignant. Regresses after cessation of the smoking habit.
      Snuff dipper's lesionSee keratotic lesions (tobacco pouch keratosis).
      Syphilis, secondary (“mucous patches”)Medical history; clinical aspect. Demonstration of Treponema pallidum; serology.
      White sponge nevusYoung age; often family history. The clinical aspect is more or less diagnostic. Occasionally a biopsy may be helpful.
      Slightly modified from Warnakulasuriya et al.
      • Warnakulasuriya S.
      • Johnson N.W.
      • van der Waal I.
      Nomenclature and classification of potentially malignant disorders of the oral mucosa.
      The definition of erythroplakia, that is, a fiery red patch that can not be characterized as any other definable disease, has remained unchanged over the years.
      • Warnakulasuriya S.
      • Johnson N.W.
      • van der Waal I.
      Nomenclature and classification of potentially malignant disorders of the oral mucosa.

      Clinical classification of leukoplakia

      In the 1960s, a 3-tier clinical classification of leukoplakia was proposed: (1) simple leukoplakia, (2) verrucous leukoplakia, and (3) erosive leukoplakia.
      • Bánóczy J.
      • Sugár L.
      Progressive and regressive changes in Hungarian oral leukoplakias in the course of longitudinal studies.
      In the 1978 WHO classification a 2-tier clinical classification was recommended—homogeneous and nonhomogeneous leukoplakia.
      • WHO Collaborating Centre for Oral Precancerous Lesions
      Definition of leukoplakia and related lesions: an aid to studies on oral precancer.
      The distinction between homogeneous and nonhomogeneous leukoplakia has been shown in most studies to be of statistical significance with regard to the prediction of malignant transformation, which is higher for the nonhomogeneous type.

      Homogeneous leukoplakia

      Some apply the term homogeneous leukoplakia only for leukoplakias that are thin and flat,
      • Axéll T.
      • Pindborg J.J.
      • Smith C.J.
      • van der Waal I.
      Oral white lesions with special reference to precancerous and tobacco-related lesions: conclusions of an international symposium held in Sweden.
      whereas others also recognize a thick type of homogeneous leukoplakia. In addition, subvariants of homogeneous leukoplakia have been reported, such as velvet-like and pumice stone–like types.

      Nonhomogeneous leukoplakia

      Nonhomogeneous leukoplakia has been subdivided into a mixed red-and-white type (erythroleukoplakia) and a verrucous type. Erythroleukoplakias may be subdivided into speckled, granular, and nodular types.
      Although having a homogeneous white color, verrucous (wart-like) leukoplakia has been classified as a subtype of nonhomogeneous leukoplakia.
      • Axéll T.
      • Pindborg J.J.
      • Smith C.J.
      • van der Waal I.
      Oral white lesions with special reference to precancerous and tobacco-related lesions: conclusions of an international symposium held in Sweden.
      In cases of widespread verrucous leukoplakia, the term proliferative verrucous leukoplakia (PVL) is often used.
      • Hansen L.S.
      • Olson J.A.
      • Silverman Jr, S.
      Proliferative verrucous carcinoma. A long-term study of thirty patients.
      Apart from being widespread, PVL also has a strong tendency to recur after treatment. In the past, the terms florid oral papillomatosis
      • Michelet F.X.
      • Garnery J.P.
      Florid oral papillomatosis.
      and verrucous hyperplasia have been used for this clinical presentation.
      • Shear M.
      • Pindborg J.J.
      Verrucous hyperplasia of the oral mucosa.

      Preleukoplakia, Keratoses

      Preleukoplakia

      There have been some reports in the literature on preleukoplakia, thought of as a precursor stage of leukoplakia and decribed as a gray or grayish-white area with indistinct borders blending into the adjacent normal mucosa.
      • Pindborg J.J.
      • Bhatt M.
      • Devenath K.R.
      • Narayana H.R.
      • Ramachandra S.
      Frequency of oral white lesions among 10,000 individuals in Bangalore, South India. A preliminary report.
      • Axéll T.
      A prevalence study of oral mucosal lesions in an adult Swedish population.
      This term may perhaps be applied to flat changes of the mucosa that are not white enough to qualify for the term leukoplakia.

      Keratoses

      The use of the term keratosis for a number of oral white lesions is somewhat confusing. In fact, keratosis is primarily a histologic term, used in cases of hyperorthokeratosis or hyperparakeratosis. In a study by Payne, it was shown that thickening of the keratin layer per se or the overall thickness of the epithelium actually may not be the primary factor in causing an intraoral lesion to appear white.
      • Payne T.F.
      Why are white lesions white?.
      Nevertheless, the term keratosis is quite commonly used by clinicians and researchers to describe an oral white plaque, whether based on biopsy findings or not.
      In some parts of South India and occasionally in other parts of the world, reversed smoking is practiced, causing often initially white changes of the palatal mucosa. The whitish changes have been referred to as reversed smoking keratosis.
      • Mehta F.S.
      • Jalnawalla P.N.
      • Daftary D.K.
      • Gupta P.C.
      • Pindborg J.J.
      Reverse smoking in Andhra Pradesh, India: variability of clinical and histologic appearances of palatal changes.
      These palatal lesions have a high risk of malignant transformation. Because they are regarded as a well-defined, known entity, they are excluded from the common category of leukoplakia.
      Sublingual keratosis refers to widespread whitish changes of the floor of the mouth, the ventral aspect of the tongue, and the lingual mucosa. A study from the United Kingdom emphasized the high risk of malignant transformation in that particular subsite of the oral cavity.
      • Kramer I.R.H.
      • El-Laban N.
      • Lee K.W.
      The clinical features and risk of malignant transformation in sublingual keratosis.
      There is, at present, no justification for the use of the term sublingual keratosis instead of leukoplakia.
      A few papers have been published on alveolar ridge keratosis.
      • Chi A.C.
      • Lambert I.I.I.P.R.
      • Pan Y.
      • et al.
      Is alveolar ridge keratosis a true leukoplakia? A clinicopathologic comparison of 2,153 lesions.
      • Natarajan E.
      • Woo S.B.
      Benign alveolar ridge keratosis (oral lichen simplex chronicus): a distinct clinicopathologic entity.
      Apparently, the supposed cause of the lesion is chronic frictional (masticatory) trauma to the maxillary and mandibular alveolar ridges, particularly in the retromolar pad and edentulous parts of the ridges. Histopathologically, almost of all these lesions show hyperkeratosis without epithelial dysplasia. The authors recommended that this lesion be removed from the category of oral leukoplakia because of its low risk of malignant transformation and to use the term benign alveolar ridge keratosis instead.
      The term frictional keratosis has been used for white lesions that are supposedly caused by friction—that is, vigorous brushing of teeth. The suggestion to remove this lesion from the category of leukoplakia
      • Mignogna M.D.
      • Fortuna G.
      • Leuci S.
      • et al.
      Frictional keratoses on the facial attached gingiva are rare clinical findings and do not belong to the category of leukoplakia.
      seems somewhat questionable. If the lesion disappears after elimination of the suggested causative habit, there should be no objection to the use of the term frictional. However, in persistent cases, the role of friction remains uncertain. In such cases, a diagnosis of leukoplakia seems preferable.
      In sanguinaria-associated keratosis, the white changes of the oral mucosa, particularly in the maxilla, are caused by sanguinaria, an herbal extract used in dentifrices and mouthrinses.
      • Eversole L.R.
      • Eversole G.M.
      • Kopcik J.
      Sanguinaria-associated oral leukoplakia: comparison with other benign and dysplastic leukoplakic lesions.
      In some cases, epithelial dysplasia was observed. There is no information on the potential for cancer development in these patients.
      In tobacco pouch keratosis, also referred to as snuff dipper's lesion, the clinical appearance may vary from a white to a more grayish coloration of the oral mucosa in direct contact with the tobacco product. The surface may be somewhat wrinkled or corrugated. Histopathologically, hyperkeratosis and acanthosis are the common features. Epithelial dysplasia is rarely encountered. The risk of malignant transformation seems to be mainly related to the type of the chewing product.
      • Rodu B.
      Smokeless tobacco and oral cancer: a review of the risks and determinants.
      Some authors have distinguished 3 types of keratosis: (1) reactive keratosis, (2) dysplastic/malignant keratosis, and (3) keratosis of unknown significance.
      • Woo S.B.
      • Grammar R.L.
      • Lerman M.A.
      Keratosis of unknown significance and leukoplakia: a preliminary study.
      The risk of possible malignant transformation of keratosis of unknown significance is still unknown.

      Discussion and Some Suggestions for Modifications of the Definition of Leukoplakia and the Clinical Classification

      In view of the increasing knowledge about carcinogenesis, including various genetic aspects, it is no surprise that suggestions already have been made to modify the definition of potentially (pre)malignantlesions and diseases. An example is the one provided by Sarode et al.: “It is a group of disorders of varying etiologies, usually tobacco, characterized by mutagen associated, spontaneous, or hereditary alterations or mutations in the genetic material of oral epithelial cells with or without clinical and histomorphological alterations that may lead to oral squamous cell carcinoma transformation.”
      • Sarode S.C.
      • Sarode G.S.
      • Tupkari J.V.
      Oral potentially disorders: precising the definition.
      It is well recognized that the discussion on leukoplakia is mainly based on its appearance in patients in the Western world. Oral leukoplakia may indeed have different characteristics in other parts of the world, such as India, because of different diets, tobacco and chewing habits, and perhaps genetic differences. In this respect, attention should be paid to a proposal from some authors from India for a new classification for potentially (pre)malignant disorders.
      • Sarode S.C.
      • Sarode G.S.
      • Karmarkar S.
      • Tupkari J.V.
      A new classification for potentially malignant disorders of the oral cavity.
      Interestingly, in this proposal, leukoplakia has been listed solely as a tobacco-associated lesion.
      The present definitions of leukoplakia and erythroplakia are only slightly different from the ones that have been used already some 50 years ago. Leukoplakia and erythroplakia are still defined by negative description, that is, by excluding other white and red lesions or disorders, respectively. The present use of the term disorder acknowledges the fact that malignant transformation may occur not only at or close to the site of the leukoplakia or erythroplakia but also elsewhere in the oral cavity in apparently clinically normal mucosa. However, the term lesion, instead of disease and disorder, is probably better understood by clinicians.
      The part of the present definition “… having excluded other known diseases or disorders that carry no increased risk for cancer” is somewhat confusing because several of the well-defined lesions listed in Table I do have (pre)malignant potential.
      In the definition of leukoplakia, one may consider including a description that the lesion cannot be wiped as has been the case in one of the early definitions, where the description “… that cannot be rubbed off …” has been included. In this way, mainly pseudomembranous candidiasis can be easily differentiated from leukoplakia. The phrase “cannot be wiped” seems to be a better description than “cannot be rubbed off.” To the best of my knowledge, there are no red lesions of the oral mucosa that can be wiped. Therefore, this aspect does not have to be mentioned in the definition of erythroplakia.
      For clinical use, there is no apparent reason to include again a minimum size (e.g., 5 mm) in the definition as has been the case in the past. Nevertheless, there may be some merit in including a minimum size of leukoplakias for reporting purposes, thereby avoiding every minute white spot of the oral mucosa being included in the study material. Additionally, for reporting purposes, the use of a level of certainty (C-factor) on which the diagnosis of leukoplakia has been based, shown in Table II, is recommended.
      • van der Waal I.
      Potentially malignant disorders of the oral and oropharyngeal mucosa: terminology, classification and present concepts of management.
      Table IICertainty (C)-factor of a diagnosis of oral leukoplakia
      C1 Evidence from a single visit, applying inspection and palpation as the only diagnosis means (provisional clinical diagnosis), including a clinical picture of the lesion.
      C2 Evidence obtained by a negative result of elimination of suspected etiologic factors, e.g., mechanical irritation, during a follow-up period of 2 to 4 weeks (definitive clinical diagnosis)
      C3 Evidence obtained by a pretreatment incisional biopsy in which, histopathologically, no definable lesion is observed (histopathologically supported diagnosis)
      C4 Evidence based on findings from surgery and pathologic examination of the resected specimen (histopathologically proven diagnosis)
      From van der Waal.
      • van der Waal I.
      Potentially malignant disorders of the oral and oropharyngeal mucosa: terminology, classification and present concepts of management.
      Clinicians are advised to perform biopsy first before elimination of possible etiologic factors, including tobacco habits. This is particularly important in case of symptoms, although a delay of several weeks or even a month does not seem to be relevant from a prognostic point of view. However, patients may not appreciate such a delay. In case of disappearance of a leukoplakic lesion within a somewhat arbitrarily chosen period of 2 to 4 weeks after elimination of a mechanical cause, the diagnosis of frictional lesion or frictional keratosis seems appropriate. For the same reason, one may apply the term smoker's lesion in case of disappearance of a leukoplakic lesion after cessation of the tobacco habit. However, most authors prefer to refer to such lesion as tobacco-associated leukoplakia.
      For pathologists it is important to know that absence of epithelial dysplasia not a diagnosis of oral leukoplakia should not remark in the histopathologic report that leukoplakia that is not potentially (pre)malignant. Of course, clinicians should know that absence of dysplasia does not preclude potential (pre)malignant .
      The various clinical subcategories of leukoplakia are probably too complex, not only at the expert level but even more so for use by dentists and oral and maxillofacial surgeons. Therefore, one may consider simplifying this classification. Homogeneous leukoplakia might then perhaps be defined as a white lesion that has a homogeneous, predominantly white or grayish-white color and which may vary in thickness and texture. As a result, the clinical presentation may range from thin, smooth, wrinkled, and corrugated to thick and/or verrucous, thus including proliferative verrucous leukoplakia. It is, in fact, unknown whether the verrucous morphology, rather than its large, widespread presentation, is the main predicting factor of malignant transformation in PVL.
      • Holmstrup P.
      • Vedtofte P.
      • Reibel J.
      • Stolze K.
      Long-term treatment outcome of oral premalignant lesions.
      The term nonhomogeneous leukoplakia might be restricted to the mixed white-and-red presentations (erythroleukoplakias), recognizing that the texture may vary from flat and smooth to speckled, granular, or nodular. It should be emphasized that clinical subdivision into homogeneous and nonhomogeneous leukoplakias has, statistically, some predictive value with regard to the risk of malignant transformation but that this subdivision is not reliable for use in the individual patient.
      It seems logical to adjust the definition of erythroplakia in accordance with the proposed modifications to the definition of leukoplakia. Clinicians should know that all erythroplakias carry a high risk of malignant transformation, if not being malignant already at the patient's first visit.
      The proposed modifications of the definitions and the clinical classification of leukoplakia and erythroplakia are presented in Table III.
      Table IIIProposed modifications of the definitions and clinical classification of leukoplakia and erythroplakia
      Definitions
      Leukoplakia: A predominantly white lesion of the oral mucosa that cannot be wiped; other, well-defined predominantly white lesions have been excluded clinically, histopathologically, or by the use of other diagnostic aids
      Erythroplakia: A red lesion of the oral mucosa; other, well-defined red lesions have been excluded clinically, histopathologically or by the use of other diagnostic aids
      Clinical classification of leukoplakia
      Homogeneous: Homogeneous white color; the thickness and texture may vary from thin, smooth, wrinkled, and corrugated to thick and/or verrucous
      Nonhomogeneous: Mixed white-and-red appearance (“erythroleukoplakia”); the surface may vary from smooth to speckled, granular, or nodular
      Note: Leukoplakia is primarily a clinical term and has no specific histology; absence of epithelial dysplasia does not preclude a diagnosis of oral leukoplakia and does not rule out potential malignant or potentially premalignant character of the lesion.

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