Oral White Lesions: A Clinical Diagnostic Decision Tree PDF

dentistry journal Review Oral White Lesions: An Updated Clinical Diagnostic Decision Tree Hamed Mortazavi 1 , Yaser Safi 2 , Maryam Baharvand 1, *, Soudeh Jafari 1 , Fahimeh Anbari 1 and Somayeh Rahmani 1 1 2 * Oral Medicine Department, School of Dentistry, Shahid Beheshti University of Medical Scie...

dentistry journal Review Oral White Lesions: An Updated Clinical Diagnostic Decision Tree Hamed Mortazavi 1 , Yaser Safi 2 , Maryam Baharvand 1, *, Soudeh Jafari 1 , Fahimeh Anbari 1 and Somayeh Rahmani 1 1 2 * Oral Medicine Department, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran; [email protected] (H.M.); [email protected] (S.J.); [email protected] (F.A.); [email protected] (S.R.) Oral and Maxillofacial Radiology Department, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran; [email protected] Correspondence: [email protected]; Tel.: +98-21-26708415 Received: 23 November 2018; Accepted: 18 January 2019; Published: 7 February 2019 !"#!$%&'(! !"#$%&' Abstract: Diagnosis of oral white lesions might be quite challenging. This review article aimed to introduce a decision tree for oral white lesions according to their clinical features. General search engines and specialized databases including PubMed, PubMed Central, EBSCO, Science Direct, Scopus, Embase, and authenticated textbooks were used to find relevant topics by means of MeSH keywords such as “mouth disease”, “oral keratosis”, “oral leukokeratosis”, and “oral leukoplakia”. Related English-language articles published since 2000 to 2017, including reviews, meta-analyses, and original papers (randomized or nonrandomized clinical trials; prospective or retrospective cohort studies), case reports, and case series about oral diseases were appraised. Upon compilation of data, oral white lesions were categorized into two major groups according to their nature of development: Congenital or acquired lesions and four subgroups: Lesions which can be scraped off or not and lesions with the special pattern or not. In total, more than 20 entities were organized in the form of a decision tree in order to help clinicians establish a logical diagnosis by a stepwise progression method. Keywords: mouth disease; oral keratosis; oral leukokeratosis; oral leukoplakia 1. Introduction Diagnosis of oral white lesions might be quite challenging. These lesions represent a wide spectrum of lesions with different etiology and various prognoses. The diagnosis of white lesions varies from benign reactive lesions to more serious dysplastic and carcinomatous lesions. While there are some classic features that help distinguish these lesions, similar features may give rise to some complications in diagnosis. Efforts should be made to establish a definite diagnosis to prevent time elapse in treatment of patients with more serious lesions. A decision tree is a flowchart that organizes features of lesions in order to help clinicians to reach a logical conclusion. To use the decision tree, one should begin from the left side of the tree, makes the first decision, and proceeds to the far right of the tree where the definite diagnoses are listed. Oral lesions can be classified into four groups comprising of ulcerations, pigmentations, exophytic lesions, and red-white lesions. Although white lesions constitute only 5% of oral pathoses, some of these lesions such as leukoplakia, lichen planus, and proliferative verrucous leukoplakia have malignant potential as high as 0.5–100%. Therefore, white lesions mandate an appropriate clinical diagnostic approach to exclude the possibility of malignancy. The onset of oral white lesions can be acquired or congenital, with a history of long-lasting existence in the latter form. Oral white lesions can be caused by a thickened keratotic layer or an accumulation Dent. J. 2019, 7, 15; doi:10.3390/dj7010015 www.mdpi.com/journal/dentistry Dent. J. 2019, 7, x FOR PEER REVIEW 2 of 24 The onset of oral white lesions can be acquired or congenital, with a history of long-lasting existence in the latter form. Oral white lesions can be caused by a thickened keratotic layer or an accumulation of non-keratotic material. Accordingly, when a clinician confronts a white area on2 the Dent. J. 2019, 7, 15 of 24 oral mucosa, the first issue to be elucidated is whether it can be scraped off by means of a piece of gauze or not. If so, a superficial non-keratotic layer such as pseudomembranes, most commonly of non-keratotic when a clinician a white area on the oral mucosa, caused by fungal material. infections Accordingly, or caustic chemicals, should beconfronts suspected. Otherwise, white lesions can theattributed first issue to elucidated is whether can be layer, scrapedwhich off bymight means have of a piece gauze or by not.local If so, be to be increased thickness of itkeratin beenofinduced a superficial non-keratotic layer suchreactions, as pseudomembranes, mostprocesses commonlysuch caused fungal infections frictional irritation, immunologic or more crucial asby premalignant or or caustictransformation chemicals, should malignant [4,5].be suspected. Otherwise, white lesions can be attributed to increased thickness keratin which might beenofinduced by local frictional irritation, immunologic In the of next step, layer, any specific clinicalhave pattern white lesions such as papular, annular, reticular or more crucial processes such as premalignant or malignant transformation [4,5]. should orreactions, erosive-ulcerative patterns, or a combination of them (characteristic for lichenoid lesions) In the next step, to any specific clinical of white lesions as papular, ones. annular, reticular or be inspected in order differentiate whitepattern patterned lesions fromsuch non-patterned erosive-ulcerative a combination of them lichenoid lesions)oral should be Therefore, thispatterns, narrativeorreview paper focuses on(characteristic three clinicalfor steps to approach white inspected order to differentiate white patterned non-patterned ones. the second and lesions: Theinfirst step is to determine whether the lesions lesion isfrom congenital or acquired; Therefore, this narrative focuses three clinical steps approach oral or white third steps are to inspect if itreview can bepaper wiped off oronnot and if it has a to special pattern not.lesions: This The first step is to determine whether the lesion is congenital or acquired; the second and third steps diagnostic process is presented as an updated clinical decision tree. A decision tree is a flowchart are tofor inspect if it canfeatures be wipedofofflesions or not or anddiseases if it has athat special or not. Thisadiagnostic process used organizing helppattern clinicians make constellation of is presented as an updated clinical decision tree. A decision tree is a flowchart used for organizing rational decisions rather than haphazard ones to reach a conclusive diagnosis. features of lesions or diseases that help clinicians make a constellation of rational decisions rather than 2.haphazard Search Strategy ones to reach a conclusive diagnosis. General search engines and specialized databases including PubMed, PubMed Central, EBSCO, 2. Search Strategy Science Direct, Scopus, Embase, and authenticated textbooks were used to find relevant topics by search enginessuch and specialized including PubMed, PubMed Central, EBSCO, meansGeneral of MeSH keywords as “mouth databases disease,” “oral keratosis,” “oral leukokeratosis,” and Science Direct, Scopus, Embase, and authenticated textbooks were used to find relevant topics “oral leukoplakia”. Related English-language articles published from 2000 to 2017 including by means of MeSH keywords such as(randomized “mouth disease,” “oral keratosis,” “oral leukokeratosis,” reviews, meta-analyses, original papers or non-randomized clinical trials; prospective “oral leukoplakia”. Related English-language articles from 2000 to more 2017 including orand retrospective cohort studies), case reports, and case series published were reviewed. Out of than 140 reviews, meta-analyses, original papers (randomized or non-randomized clinical trials; prospective relevant articles and textbooks, five textbooks, and 45 papers were selected including reviews, caseor retrospective cohort studies), case reports, andWe casedescribed series were Out offocus moreon than 140 clinical relevant reports or case series, and original articles. 20reviewed. entities, with their articles and textbooks, five textbooks, and 45 papers were selected including reviews, case reports aspects. Finally, oral white lesions were categorized into two major groups of congenital andor case series, and original We described 20 entities, focus on clinical Finally, acquired origin and fourarticles. subgroups: those that can be with scrapped off their or not, andaspects. patterned or oral white lesions were categorized into two major groups of congenital and acquired origin and four non-pattern lesions (Figure 1). subgroups: scrapped off orwere not, and patterned or non-pattern (Figure 1). Picturesthose usedthat in can thisbereview article collected from the archivelesions of Oral Medicine Pictures used in this review article were collected from the archive of Oral Medicine Department Department of Shahid Beheshti Dental School under permission of the patients by signing the of Shahid Beheshti Dental School under permission of the patients by signing the special consent form. special consent form. Figure1.1.Decision Decisiontree treeofoforal oralwhite whitelesions. lesions. Figure Dent. J. 2019, 7, 15 3 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 3 of 24 3. Congenital/Genetically Lesions 3. Congenital/Genetically Lesions 3.1. Leukoedema 3.1. Leukoedema Leukoedema is ais common of the the oral oralmucosa. mucosa. The prevalence Leukoedema a commonnormal normal variation variation of The prevalence has has been been reported up to 90% among blacks and between 10–50% in whites, with no sex predilection reported up to 90% among blacks and between 10–50% in whites, with no sex predilection [4–6].[4–6]. Higher prevalence among blacks is possibly due to more pigmentation making this condition Higher prevalence among blacks is possibly due to mucosal more mucosal pigmentation making this It is more distinct in smokers;after however, aftercessation, smoking cessation, it less morecondition apparentmore. Itapparent is more. distinct in smokers; however, smoking it becomes becomes less obvious. It seems to be a developmental variation with an unknown etiology [4,5]. obvious. It seems to be a developmental variation with an unknown etiology [4,5]. Clinically it presents Clinically it presents asnon-scrapable a diffuse, gray and to white, non-scrapable veil-like condition, which be and as a diffuse, gray to white, veil-like condition,and which can be described as acan milky described as a milky and opalescent transformation of the oral mucosa. In more prominent cases, opalescent transformation of the oral mucosa. In more prominent cases, leukoedema is characterized leukoedema is characterized by mucosal folds along with wrinkles or whitish streaks. This condition by mucosal folds along with wrinkles or whitish streaks. This condition usually disappears temporarily usually disappears temporarily after gentle stretching of the mucosa, which reappears after quitting after the gentle stretching of the mucosa, which reappears after quitting the manipulation (Figure 2). manipulation (Figure 2). (A) (B) Figure 2. Leukoedema: (A) White appearance of buccal mucosa to Leukoedema. By Figure 2. Leukoedema: (A) White appearance of buccal mucosa due todue Leukoedema. (B) By(B) stretching stretching the mucosa, the white wrinkled area disappeared. the mucosa, the white wrinkled area disappeared. Leukoedema ofteninvolves involves the mucosa and sometimes the lateral the tongue Leukoedema often thebuccal buccal mucosa and sometimes theborders lateralofborders of the bilaterally. It may spread to the labial mucosa and rarely affects the floor of the mouth, tongue bilaterally. It may spread to the labial mucosa and rarely affects the floor of the mouth, palatopharyngeal and laryngeal tissues [4–6,7]. Some extra oral mucosa such as vagina might also be palatopharyngeal and laryngeal tissues [4–7]. Some extra oral mucosa such as vagina might affected. Leukoedema is asymptomatic with no potential for malignant transformation. No also be affected. Leukoedema is asymptomatic treatment is required for this condition [4,5,7] (Tablewith 1). no potential for malignant transformation. No treatment is required for this condition [4,5,7] (Table 1). Table 1. Characteristics of congenital/genetically white lesions. Entity Age Leukoedema Not Assigned (NA) White sponge nevus presents at birth Common Location Clinical Features Treatment Premalignant M=F buccal mucosal folds, wrinkled white strerias NA NA NA buccal, ventral surface of the tongue, labial mucosa, soft palate, alveolar mucosa, floor of the mouth symmetrical, thickened, white, corrugated or velvety, diffuse spongy plaques with an elevated, irregular and fissural surface NA NA bullae formation, erosions, leukoplakic lesions, rapidly progressive periodontal disease, gingival inflammation and bleeding, gingival recession, bone loss, decreased root/crown ratio, mild taurodontism bone marrow transplantation (BMT), androgens, oral and topical vitamin E 30% malignant transformation in leukoplakia opalescent appearance mimicking leukoedema/thick, corrugated white plaques NA NA Gender Dyskeratosis congenita 5–12 years NA buccal, tongue, oropharynx Hereditary benign intra epithelial dyskeratosis childhood NA buccal, labial Dent. J. 2019, 7, 15 4 of 24 3.2. White Sponge Nevus White sponge nevus (WSN), also called Cannon disease or familial white folded dysplasia, is an inherited autosomal dominant disorder that is defined as dyskeratotic hyperplasia of mucous membranes. WSN is a rare condition with no sex predilection. A prevalence of below one in 200,000 population has been reported. The lesions generally present at birth or early in childhood, but sometimes the condition appears during adolescence [5,7]. Mutations in keratin genes are responsible for coding of epithelial keratin types K4 and K13 results in lack of normal keratinization [4,5]. Both intraoral and extra oral mucosal sites might be involved. Intraoral lesions are symmetrical, thickened, white, corrugated or velvety, diffuse, spongy plaques of variable sizes with an elevated, irregular, and fissural surface. Buccal mucosa is affected bilaterally in most patients [4,5,7,8]. Other areas of the oral cavity such as the ventral surface of the tongue, labial mucosa, soft palate, alveolar mucosa, and floor of the mouth can also be affected, but the amount of involvement might vary from patient to patient. Extraoral sites include nasal, esophageal, laryngeal, and anogenital mucosa; however, their involvement is relatively unusual in the absence of oral manifestations. White sponge nevus can cause dysphagia when the esophagus is involved; otherwise, the lesions are asymptomatic [4,5]. Due to the benign nature of the lesion, good prognosis, and infrequent recurrence rate no treatment is suggested for WSN [3,4,7] (Table 1). 3.3. Dyskeratosis Congenita Dyskeratosis congenita (DC), also called Coleengman syndrome or Zinsser-Colleengman syndrome, is a bone marrow failure (BMF) syndrome inherited as an X-linked recessive trait with a marked male predilection and women showing less serious clinical manifestations. Infrequent cases of autosomal dominant and autosomal recessive forms have been reported as well [5,9]. Defects in telomere preservation, which protects chromosomal ends against deterioration and inappropriate recombination lead to dyskeratosis congenita [10,11]. This is a rare condition with the annual incidence rate of one per one million population It usually emerges between the ages of 5 to 12 years. Clinical manifestations of DC might be quite various such as abnormal skin pigmentation, nail dystrophy (approximately 90%), oral premalignant leukoplakia (approximately 80%), BMF, cancer susceptibility with elevated risk for squamous cell carcinoma, and hematolymphoid neoplasms [4,9]. Other reported manifestations are intrauterine growth retardation, developmental delay, microcephaly, eyes and hair abnormalities, like premature graying, extreme sweating, short stature, hypogonadism, enteropathy, liver disease, esophageal and urethral stenosis, osteoporosis, and avascular necrosis of the hips and shoulders. The most important oral manifestations are bullae formation followed by erosions, which ultimately progress to leukoplakic lesions in the buccal mucosa, tongue, and oropharynx as well as rapidly progressive periodontal disease, gingival inflammation and bleeding, gingival recession, bone loss, decreased root/crown ratio, and mild taurodontism. The treatment is usually directed to the alleviation of symptoms. Malignant transformation is reported in approximately 30% of the leukoplakic lesions with a progression to Oral Squamous Cell Carcinoma (OSCC) within 10–30 years. Therefore, the physician should schedule frequent monitoring and biopsy taking of suspicious lesions for early diagnosis of potential malignant transformations [4,9,10]. In other words, dyskeratosis congenita is a multi-organ-system disorder that needs regular follow-ups. In severe conditions, patients live approximately 32 years. The patient and the family should receive a genetic consultation. Bone marrow failure is one of the most prevalent and main causes of death, which mandates allogeneic hematopoietic stem cell transplantation as the only main treatment. Less successful treatments such as androgens and oral and topical vitamin E have also been suggested for DC [5,9] (Table 1). Dent. J. 2019, 7, 15 5 of 24 3.4. Hereditary Benign Intraepithelial Dyskeratosis Hereditary benign intraepithelial dyskeratosis (HBID) also called Witkop-Von Sallmann syndrome is a rare autosomal-dominant disorder of the conjunctiva and oral mucosa. This condition primarily reported in descendants of tri-racial isolate (European-American, African-American, and Native American descents) in North Carolina; however, some examples of HBID have been reported sporadically from other areas of the United States, which might be due to migration of affected people. On the other hand, no history of migration to the United States was found in some patients [5,12]. This disorder progresses during childhood with oral manifestations being similar to WSN as thick, corrugated white plaques affecting the buccal and labial mucosa. Milder cases show an opalescent appearance mimicking leukoedema. Other oral mucosal areas such as the floor of the mouth and lateral borders of the tongue might also be involved. Candida species can superimpose on these lesions thereafter. Another clinical manifestation of HBID is ocular lesions presenting as white thick opaque gelatinous plaques on the bulbar conjunctiva adjacent to the cornea with occasional corneal involvement. Eye lesions are found very early in life and increase over time. Patients might complain from tearing, photophobia, and itching of the eyes when the lesions are active. In many cases, the plaques are more obvious in the spring, but they show seasonal regression during summer or autumn. Corneal involvement can result in visual impairment and blindness [5,10,12]. Hereditary benign intraepithelial dyskeratosis is a benign lesion in the oral cavity; hence no treatment modality is needed unless a superimposed infection with candida occurs, which requires antifungal therapy. In case of symptomatic ocular involvement, an ophthalmologist must evaluate the eyes. Generally, eye plaques influencing visual ability should be excised surgically, however these lesions commonly re-appear (Table 1). 4. Acquired Lesions That Can Be Scraped Off 4.1. Superficial Oral Burn Oral burn includes thermal and chemical burns of the oral cavity. Intraoral thermal burns have been reported frequently, while the chemical injury is not common. Thermal burns of the oral cavity generally result from ingestion of hot foods or beverages like hot pizza or coffee. Extended use of microwave ovens has caused an increased prevalence of thermal burns since they heat up food unevenly in a way that the inner portion of it remains cold while the other part becomes hot [4,5,14]. The most commonly affected areas are palatal mucosa, posterior buccal mucosa, and the anterior part of the tongue. Keratinized mucosa is more resistant to burn than non-keratinized lining mucosa. The extension of injury is related to temperature and duration of contact [5,15]. There is an iatrogenic reason for thermal injury due to accidental contact with hot dental instruments. When the mucosa is anesthetized, the contact with hot instruments might continue longer, which results in more extensive burn injury. On the other hand, chemical burns can result from the use of chemical materials like topical applications of medications to relieve dental pain (Figure 3). Dent. J. 2019, 7, 15 6 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 6 of 24 Figure 3. 3. Superficial Superficial oral oral burn burn due Figure due to to placement placement of of an an over-the-counter over-the-counteranaesthetic anaestheticgel. gel. Someof ofwell-documented well-documented caustic materials Some materials are are aspirin, aspirin,sodium sodiumperborate, perborate,hydrogen hydrogenperoxide, peroxide, gasoline, turpentine, turpentine, rubbing rubbing alcohol, battery acid, gasoline, acid, isopropyl isopropyl alcohol, alcohol, phenol, phenol, eugenol, eugenol,carbamide carbamide peroxidase,bisphosphonates, bisphosphonates, chlorpromazine, chlorpromazine, and peroxidase, and promazine promazine[5,13]. [5,13].Thermal Thermalburn burnusually usuallyisismild mild and affects just a small area as a sloughy yellow-white necrotic epithelium with areas and affects just a small area as a sloughy yellow-white necrotic epithelium with areasofoferythema erythema andulceration ulceration[5,13,14]. [5,13,14].However, However, chemical burns result in mucosal necrosis with severe more severe and chemical burns result in mucosal necrosis with more clinical clinical features. In case of short-time exposure to chemicals, the superficial mucosa becomes features. In case of short-time exposure to chemicals, the superficial mucosa becomes white white and wrinkled, but longer exposures lead to of denudation of the layer andof and wrinkled, but longer exposures lead to denudation the epithelial layerepithelial and development development of a yellowish, fibrinopurulent membrane over the area. Most cases of mucosal a yellowish, fibrinopurulent membrane over the area. Most cases of mucosal burns have little burns have little clinical effects and improve without treatment [5,13]. Use of rubber dam is a clinical effects and improve without treatment [5,13]. Use of rubber dam is a preventive technique preventive in order tomucosal decreaseburns iatrogenic burns. size According to the sizeofand in order to technique decrease iatrogenic. mucosal According to the and symptoms the symptoms of the lesions, some recommendations are proposed to manage these conditions such as lesions, some recommendations are proposed to manage these conditions such as use of non-steroidal use of non-steroidal anti-inflammatory drugsantiseptic (NSAID’s), antibiotics, coverage antisepticwith mouthwashes, anti-inflammatory drugs (NSAID’s), antibiotics, mouthwashes, a protective coverage with a protective emollient paste or a hydroxypropyl cellulose film, topical anesthetics, emollient paste or a hydroxypropyl cellulose film, topical anesthetics, and surgical debridement [5,15] and surgical debridement [5,15] (Table 2). (Table 2). Table 2. Characteristics of acquired white lesions that can be scraped off. Entity Age Gender Common Location Clinical Features Treatment Premalignant Superficial burn NA NA palatal, posterior buccal, anterior tongue sloughy yellow-white necrotic epithelium with the areas of erythema and ulceration NSAIDs, antiseptics, antibiotics, analgesics NA infants/elderly F>M buccal, tongue, palate creamy white plaques, patches, or papules antifungals NA NA NA NA a white, dirty yellow-white or grayish-white color removal of the debris, oral rinses NA F>M buccal, lips, lateral border of the tongue shaggy and thickened macerated gray-white patches or plaques with keratin shreds, tissue tags or desquamated areas cessation the habitual chewing NA psuedomembranous candidiasis Pseudomembrane of oral ulcers and materia alba Morsicatio >35 years 4.2. Pseudomembranous Candidiasis Oral candidiasis is the most common fungal infection of the oral cavity mostly caused by Candida Albicans as one of the normal microflora organisms [4,16]. It can be isolated from almost 50% of Morsicatio >35 years F>M border of the tongue plaques with keratin shreds, tissue tags or desquamated areas habitual chewing 4.2. Pseudomembranous Candidiasis Dent. J. 2019, 7, 15 NA 7 of 24 Oral candidiasis is the most common fungal infection of the oral cavity mostly caused by Candida Albicans as one of the normal microflora organisms [4,16]. It can be isolated from almost 50% dentate patients andand more thanthan 60%60% of edentulous individuals with awith female predilection. The acute of dentate patients more of edentulous individuals a female predilection. The pseudomembranous form of oral candidiasis is usually seen in infants due to their underdeveloped acute pseudomembranous form of oral candidiasis is usually seen in infants due to their immune system, the elderlysystem, becausethe of elderly their compromised immunity and patients on broad-spectrum underdeveloped immune because of their compromised immunity and patients antibiotics [4,17] (Figure 4). on broad-spectrum antibiotics [4,17] (Figure 4).. Figure candidiasis due todue using membranes Figure 4.4.Pseudomembranous Pseudomembranous candidiasis to broad usingspectrum broad antibiotic; spectrum pseudo antibiotic; pseudo can be scraped a pieceoff of by gauze. membranes canoff beby scraped a piece of gauze. ItItpresents creamy white plaques, patches, or papules that can be wiped an erythematous presentsas as creamy white plaques, patches, or papules that canoff bewith wiped off with an and sometimes and bleeding area leaving behind [4,5,17]. The classic [4,5,17]. appearance pseudomembranous erythematous sometimes bleeding area leaving behind Theofclassic appearance of candidiasis is called “curdled milk” Burning sensation foul tastesensation might accompany the lesions pseudomembranous candidiasis is. called “curdled milk” and. Burning and foul taste might as well. The chronic pseudomembranous oral candidiasis is not distinguishable from its isacute accompany the lesions as well. The chronic pseudomembranous oral candidiasis not counterpart that emerges in patients with HIV infection and those taking corticosteroid inhalers. distinguishable from its acute counterpart that emerges in patients with HIV infection and those The buccal mucosa is frequently affected by pseudomembranous candidiasis followed by the tongue taking corticosteroid inhalers. The buccal mucosa is frequently affected by pseudomembranous and the palate. Elimination predisposing factors,Elimination if possible, is cornerstone of treatment along candidiasis followed by theof tongue and the palate. ofthe predisposing factors, if possible, is with antifungal regimen (Table 2). the cornerstone of treatment along with antifungal regimen (Table 2). 4.3. Pseudomembrane of Oral Ulcers and Materia Alba 4.3. Pseudomembrane of Oral Ulcers and Materia Alba An epithelial defect in the ulcerative process is usually coated by a pseudomembrane composed of necrotic cells and fibrin. It is usually seen in aphthous ulcers, erythema multiforme, and other ulcerative conditions of the oral cavity. The color of a fibrin clot is white, dirty yellow-white, or grayish-white [4,18]. Materia Alba is defined as accumulated oral debris resulting from poor oral hygiene forming a plaque-like appearance such as a coated tongue. Sometimes this condition is misdiagnosed with other pathologic white lesions. Both pseudomembrane and material alba can be easily wiped off. Under the pseudomembrane, a raw, bleeding, and painful surface appears while wiping materia alba leaves a quite normal mucosa underneath [18–20] (Table 2). 4.4. Morsicatio Morsicatio originates from the Latin word morsus, meaning “bite”, which also called morsicatio mucosa oris or chronic mucosal chewing. This lesion is caused by self-induced injury and chronic tissue irritation like habitual chewing of buccal mucosa, chronic nibbling, biting, or sucking (Figure 5). 4.4. Morsicatio Morsicatio originates from the Latin word morsus, meaning “bite”, which also called morsicatio mucosa oris or chronic mucosal chewing. This lesion is caused by self-induced injury and chronic tissueJ. 2019, irritation Dent. 7, 15 like habitual chewing of buccal mucosa, chronic nibbling, biting, or sucking (Figure 8 of 24 5). Figure Figure 5. 5. Habitual Habitual biting biting of of cheeks cheeks and and the the lower lower lip. lip. Most patients patientsdeny denythe the self-inflicted injury or itdo it subconsciously. Glass blowers self-inflicted injury or do subconsciously. Glass blowers developdevelop similar similar in theirmucosa buccal mucosa due toirritation chronic irritation as well. The prevalence of morsicatio changeschanges in their buccal due to chronic as well. The prevalence of morsicatio has been has been 0.5% reported 0.5%among to 1.12% among population the generalwith population a male ratio of 1/3. reported to 1.12% the general a male towith female ratioto of female 1/3. This condition This condition common in patients older years, andstress thoseorhaving or is more commonisinmore patients older than 35 years, and than those 35 having extra mentalextra illnessstress [4,5,21]. mental illness [4,5,21]. The most affected areas are non-keratinized epithelium of the buccal mucosa The most affected areas are non-keratinized epithelium of the buccal mucosa (morsicatio buccarum), (morsicatio buccarum), lipsand (morsicatio labiorum), lateral borders oflinguarum), the tongue respectively. (morsicatio lips (morsicatio labiorum), the lateral borders ofand thethe tongue (morsicatio linguarum), respectively. Morsicatio does not involve areas not achievable to habitual chewing Morsicatio does not involve areas not achievable to habitual chewing trauma [4,5,14,21]. While the trauma [4,5,14,21]. Whilebilaterally the lesions present bilaterally on buccal the mid-portion of anterior buccal lesions usually present onusually the mid-portion of anterior mucosa along the occlusal mucosa alonglesions the occlusal line larger extensive may involve larger areas of buccal line extensive may involve areaslesions of buccal mucosa. Sometimes morsicatio mightmucosa. appear Sometimes might appear as unilateral lip and/or tongue lesions. The clinical features as unilateralmorsicatio lip and/or tongue lesions. The clinical features include asymptomatic shaggy and include asymptomatic shaggy and thickened macerated patches ortags, plaques with keratin thickened macerated gray-white patches or plaques with gray-white keratin shreds, tissue or desquamated shreds, tags, surface, or desquamated areas on the the mucosal surface, gradually merge the areas on tissue the mucosal which gradually merge adjacent mucosawhich [4,14,21]. A peeling irregular adjacent mucosa [4,14,21]. A peeling irregular not ragged surface with erythema or erosion—but not ragged surface with erythema or erosion—but ulceration—might accompany white areas, and ulceration—might accompany whitetoareas, and theofpatient may portion report the ability to peel shreds of the patient may report the ability peel shreds the white from the periphery of the the white portion from the periphery of the [4,5,21]. If theand clinical presentation of morsicatio lesions [4,5,21]. If the clinical presentation oflesions morsicatio is typical history taking reveals patients’ is typical and history taking reveals patients’ habit of mucosal biting the diagnosis will habit of mucosal biting the diagnosis will be established. In case of any doubt, a biopsy seems to be established. In case of condition any doubt, biopsy seemsnegative to be necessary [4,5,21]. condition has no necessary [4,5,21]. This hasa no long-term consequences and This generally no treatment long-term negative consequences and generally no treatment is recommended. As morsicatio is recommended. As morsicatio usually occurs subconsciously, the patients should give consultation usually subconsciously, theresolve patients should giveinconsultation theirchewing parafunctional for their occurs parafunctional behavior to it. Nonetheless some patientsfor whose habit is difficult to quit use of night guard has been suggested to eliminate the injury of adjacent teeth to oral mucosa [4,5,14] (Table 2). 5. Acquired Lesions That Cannot Be Scraped Off (With Specific Pattern) 5.1. Lichenoid Reactions Lichenoid reactions represent a family of lesions with different etiologies, but the same clinical and histologic appearance. Neither clinical nor histopathologic features enable the clinicians to discriminate between different lichenoid reactions (Table 3). Dent. J. 2019, 7, 15 9 of 24 Table 3. Characteristics of acquired white lesions that cannot be scraped off, with specific pattern. Entity Lichen planus Age middle age, mean age of 55 Common Location Clinical Features Treatment Premalignant F>M posterior buccal mucosa bilaterally papular, reticular, plaque-like, bullous, erythematous and ulcerative features; white components might be seen as papules, plaques, and reticular areas topical steroid, concurrent use of antifungal drugs potentially malignant disorder same reaction patterns as seen in OLP, that is, reticulum, papules, plaque, erythema, and ulcers replacement of dental materials NA NA Gender LCR NA F restricted to sites that are regularly in contact with dental materials such as buccal mucosa and lateral borders of the tongue DILR NA NA NA unilateral with an ulcerative reaction pattern withdrawal of the drug and use of topical steroids GVHD NA NA tongue and buccal mucosa hyperkeratotic reticulations and plaques, erythematous changes, and ulcerations systemic corticosteroids and/or other NA immunomodulatory agents palate, buccal mucosa, and gingivae ulcerations, erythematous lesions, hyperkeratosis, honeycomb plaque and discoid lesions as whitish steriae generally radiating from the central erythematous area (brush border) SLE mean age: 31 F NSAIDs along with antimalarial agents, systemic corticosteroids in combination with other immunosuppressives and immune modulating agents NA 5.2. Oral Lichen Planus Lichen planus (LP) is defined as a common chronic mucocutaneous disease with unknown etiology. Oral lichen planus (OLP) involves 0.1–2.2% of general population and mostly arises after middle age with a mean age of 55 years. Women are affected more frequently than men with a female to male ratio of 3:2 [4,5,22]. The mostly affected extra oral mucosal site is the genitalia. Cutaneous lesions can be detected in approximately 15% of patients [4,5,22]. Although the etiology is multifactorial, imbalanced immune system with the presence of autoreactive T lymphocytes plays a principal role in the evolution of this disease. Other factors such as stress have also been noticed in the development of this inflammatory process [4,7]. Oral lichen planus has various clinical manifestations including papular, reticular, plaque-like, bullous, erythematous, and ulcerative features [4,22]. White components might be seen as papules, plaques, and reticular areas. Generally, the papular type of OLP is found in the primary phase of the disease. Then, small white papules are usually combined together to form the reticular pattern. Fine white lines or striae (also mentioned as Wickham’s striae) comprise the reticular feature of OLP, which might form a network or annular (circular) form (Figure 6). Dent. J. 2019, 7, 15 10 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 10 of 24 (A) (B) Figure6.6.Clinical Clinicalfeatures features oral lichen planus with specific white pattern, (A) reticular the Figure of of oral lichen planus with specific white pattern, (A) reticular OLP; OLP; the arrow arrowannular shows annular form; (B) plaque-like shows form; (B) plaque-like OLP. OLP. Frequently, area. Reticular ReticularOLP OLPoften oftenaffects affects Frequently,the thestriae striaeaccompany accompanyaasurrounding surrounding erythematous erythematous area. theposterior posteriorbuccal buccal mucosa mucosa bilaterally, bilaterally, sometimes sometimes the the lateral lateral and the and dorsal dorsal tongue, tongue, the the gingiva, gingiva,the the palate,and andinfrequently infrequently the the mucosal mucosal side side and and vermilion vermilion border of the lips [4,5,7,22]. Plaque-type palate, Plaque-type OLPappears appearsas asaahomogeneous homogeneouswell-demarcated well-demarcated white plaque with peripheral OLP peripheral striae. striae. OLP OLPlesions lesions onthe thedorsum dorsumof ofthe thetongue tongue become become clear clear as as keratotic keratotic white plaques on plaques with with glossitis glossitis without withoutany any striae [4,5]. Erythematous (atrophic), bullous, and ulcerative forms of OLP are less common and striae [4,5]. Erythematous bullous, and ulcerative forms of OLP are less common and oftensurrounded surroundedby byaawhite whitereticular reticular network. network. Sometimes the erythematous often erythematous OLP OLPinvolves involvesattached attached gingivae without any papules or striae, which is called desquamative gingivitis. The reticular, gingivae without any papules or striae, which is called desquamative gingivitis. The reticular, papular, papular, and plaque-like forms of OLP commonly presentany without any symptoms, a brief and plaque-like forms of OLP commonly present without symptoms, except for except a brief for roughness. roughness. Patients with the erythematous form of OLP feel a burning sensation during eating, however, the most debilitating form of OLP is ulcerative type [4,5,17]. The presence of papules or Dent. J. 2019, 7, 15 11 of 24 Patients with the erythematous form of OLP feel a burning sensation during eating, however, the most debilitating form of OLP is ulcerative type [4,5,17]. The presence of papules or reticular elements helps clinicians establish an accurate clinical diagnosis. These characteristic components may be obvious in conjunction with plaque-like, erythematous, bullous, or ulcerative lesions. A biopsy is mandatory in gingival erythematous lesions with no obvious striae or papules to achieve a correct diagnosis [4,17]. Reticular symptomless type of OLP requires no treatment. In some patients superimposition of Candida species may cause a burning feeling of the oral mucosa, which makes the use of antifungal agents necessary. Erosive lichen planus often has symptoms such as pain and burning. A topical steroid with concurrent use of antifungal drugs is the first line of management. Systemic steroids are advised to reduce symptoms of resistant lesions. Other proposed treatments include calcineurin inhibitors, retinoids, and ultraviolet phototherapy [4,5,7,17,22,23]. OLP is considered as a potentially malignant disorder with a low risk (approximately 0.2% per year) of malignant transformation to OSCC. Therefore, precise annual monitoring of these patients is advocated [4,5,22,24]. It has been reported that plaques, erosive and ulcerative sites, especially on the soft palate, lateral, and ventral surface of the tongue or floor of the mouth show more tendency for malignant transformation, and biopsy should be considered to exclude dysplasia or carcinoma [4,5,17]. 5.3. Oral Lichen Planus Associated with Underlying Diseases Some systemic diseases and medical conditions copy the same clinical appearance of OLP. Recent studies have noticed the relationship between OLP and hepatitis C virus in some populations such as Central and Eastern Asia, Middle East, North Africa with high prevalence (over 3.5%), South Asia, sub-Saharan Africa, Central and Latin America, the Caribbean, Oceania, Australia, Central and Eastern Europe, Western Europe with medium prevalence (1.5–3.5%), and North America, Northern Europe with low prevalence (below 1.5%) [11,25]. Genetic divergence has been considered as an explanation for these differences [1,5]. Dyslipidemia is another condition which reported being significantly associated with OLP with a prevalence of 58% in OLP patients. It is shown that chronic inflammation results in disruptions in the lipid metabolism like reducing high-density lipoproteins–cholesterol (HDL-C), increasing very low-density lipoprotein-cholesterol (VLDL-C) and hypertriglyceridemia [26,27]. In addition, a relationship between thyroid disease and OLP especially hypothyroidism has been proposed. Significantly increased amounts of serum anti-thyroglobulin, autoantibodies and anti-thyroid microsomal autoantibodies were found in these patients. The prevalence of thyroid disease in patients with OLP has been reported 2.19% to 6.46%. Moreover, OLP has been found to have a major correlation with diabetes mellitus (DM), which might be due to endocrine dysfunction and immunological defects. A recent meta-analysis study showed the prevalence of OLP was 1.37% in DM patients and 0.75% in control subjects. 5.4. Lichenoid Contact Reactions Lichenoid Contact Reactions are considered to be a delayed hypersensitivity reaction to constituents derived from dental materials. Since the majority of patients show a positive patch-test to mercury, LCR is considered an allergic reaction. Nearly all dental restorative materials, except for precious metals such as titanium, palladium, and zirconium might give rise to LCRs [4,5,30] (Figure 7). Dent. J. 2019, 7, 15 Dent. J. 2019, 7, x FOR PEER REVIEW 12 of 24 12 of 24 Figure 7. Lichenoid contact reaction in buccal mucosa and alveolar ridge due to amalgam build-up of 1st and 2nd mandibular molar. molar. No prevalence forfor LCR yet.yet. Women are are affected moremore frequently than than men. No prevalence rate ratehas hasbeen beenreported reported LCR Women affected frequently Clinically, LCRs show same as seen in is, reticulum, papules, plaques, men. Clinically, LCRs the show thefeatures same features as OLP, seen that in OLP, that is, reticulum, papules,erythema, plaques, and ulcers and [4,5].ulcers The most difference OLP and LCR is the of erythema, [4,5]. apparent The mostclinical apparent clinicalbetween difference between OLP andextension LCR is the the lesions.ofThe LCRs are confined to are sitesconfined just in contact with materials, as extension themajority lesions. of The majority of LCRs to sites justdental in contact withsuch dental the buccalsuch mucosa andbuccal the lateral borders of the tongue. Lesions hardlyLesions ever observed in sites materials, as the mucosa and the lateral borders of theare tongue. are hardly ever such as the mucosa, floor of mucosa, the mouth, orof dorsum of theortongue. are observed in gingivae, sites suchpalatal as the gingivae, palatal floor the mouth, dorsumMost of theLCRs tongue. non-symptomatic, but the patient but might discomfort fromdiscomfort spicy andfrom hot food the Most LCRs are non-symptomatic, theexperience patient might experience spicywhen and hot lesionwhen converts erythematous or erythematous ulcerative forms. duration of contact with dental materialwith has food the to lesion converts to or The ulcerative forms. The duration of contact the keymaterial role to develop LCRs ontothe oral mucosa. Lichenoid reactionsLichenoid caused byreactions dental composites dental has the key role develop LCRs on the oral mucosa. caused by have been observed on the been mucosal side of both upper and lower lips. dental materials dental composites have observed on the mucosal side ofReplacement both upperofand lower lips. in direct contact with LCR will result in cure or considerable improvement in at least 90% of the Replacement of dental materials in direct contact with LCR will result in cure or considerable cases within one However, is not necessary to replace improvement in to at two leastmonths 90% of[4,5,30]. the cases within itone to two months [4,5,30].restorative However,materials it is not that are not in direct contact with LCRs. While a malignant potential for LCRs has been suggested, necessary to replace restorative materials that are not in direct contact with LCRs. While a malignant no prospective studies conducted to support studies this hypothesis.conducted to support this potential for LCRs has have been been suggested, no prospective have been hypothesis. 5.5. Drug-Induced Lichenoid Reactions 5.5. Drug-Induced Lichenoid Reactions Drug-Induced Lichenoid Reactions (DILRs) are related to a delayed hypersensitivity reaction. It hasDrug-Induced been suggested that drugs or their metabolites precipitate the lichenoid reaction. reaction. DILRs are Lichenoid Reactions (DILRs) are related to a delayed hypersensitivity It uncommon and account for a very low percentage of this entity. There are many drugs has been suggested that drugs or their metabolites precipitate the lichenoid reaction. DILRs are responsible for development of these suchofas this non-steroidal drugs uncommon andthe account for a very low lesions percentage entity.anti-inflammatory There are many drugs and angiotensin-converting enzyme inhibitors. Other medications,anti-inflammatory such as anti-malarial and responsible for the development of these lesions such as non-steroidal drugs and antihypertensive drugs, diuretics, oral hypoglycemic agents, gold salts, penicillamine, and beta angiotensin-converting enzyme inhibitors. Other medications, such as anti-malarial and blockers are also related the evolution DILRs. DILRs aregold mostly unilateral with an ulcerative antihypertensive drugs,todiuretics, oral of hypoglycemic agents, salts, penicillamine, and beta pattern, which might be quite similar to OLP. Usually the lesions evolve several months blockers are also related to the evolution of DILRs. DILRs are mostly unilateral after with the an patient starts a newwhich drug. might DILRs be arequite not generally if alesions patientevolve has serious symptoms ulcerative pattern, similar tosevere; OLP. however, Usually the several months withdrawal of the druga and of topical are often recommended.if a patient has serious after the patient starts newuse drug. DILRs steroids are not generally severe; however, symptoms withdrawal of the drug and use of topical steroids are often recommended. 5.6. Graft-Versus-Host Disease (GVHD) 5.6. Graft-Versus-Host Disease (GVHD) Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation. Oral GVHD mimics clinical features of OLP, but with a more generalized distribution Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation. Oral GVHD mimics clinical features of OLP, but with a more generalized distribution and concomitant involvement of other organs such as skin and liver. Oral Dent. J. 2019, 7, 15 13 of 24 and concomitant involvement of other organs such as skin and liver. Oral manifestations of GVHD are found in 25–70% of the patients, which might appear as the only clinical feature of GVHD. It is characterized by lichenoid inflammation that can involve all intraoral sites, but particularly affects the tongue, buccal mucosa and lips. Clinical signs ranged from only mild reticulation to more extensive disease with painful ulcerations. The soft palate is infrequently affected and it rarely extends posteriorly to the oropharynx. Treatment of GVHD, especially when there is a multisystem involvement requires systemic corticosteroids and/or other immunomodulatory agents. 5.7. Lupus Erythematosus Lupus erythematosus (LE) is an autoimmune disease classified into systemic lupus erythematosus (SLE), chronic cutaneous lupus erythematosus (CCLE), and subacute cutaneous lupus erythematosus (SCLE). SLE is a multisystem disorder with oral involvement, while CCLE involves the skin and oral mucosa. The clinical manifestations of SCLE are intermediate compared to the aforementioned types. The prevalence of LE in the United States is more than 1.5 million patients. SLE affects nearly 1 in every 2000 people with a female to male ratio of 9:1 and the mean age of 31 years at the time of diagnosis. The etiology remains unknown, however increased action of B lymphocytes and autoantibody production with the imbalanced function of T lymphocytes have been identified. Genetic and environmental factors such as infections mostly with EBV and other viruses, contact with pollutants, hormonal factors, ultraviolet light, smoking, diet, and use of some drugs are the predisposing factors for this condition [4,5]. There is an extensive range of clinical symptoms for SLE. Skin lesions (85%) include characteristic butterfly rash (40–50%), alopecia, photosensitivity, Raynaud’s phenomenon, livedo reticularis, urticaria, erythema, telangiectasia’s and, cutaneous vasculitis. Sunlight often aggravates the malar rash [4,5]. Involvement of kidneys (50–60%), musculoskeletal system (95%), central nervous system (CNS) (20%) and cardiovascular system, coagulation disorders, fatigue, depression and fibromyalgia-like symptoms, serositis, gastrointestinal and ophtalmic disorders have also been reported. Oral manifestations (9–45% in SLE, 3–20% in CCLE) include ulcerations, erythematous lesions, hyperkeratosis, honeycomb plaques, and discoid lesions. The lesions generally involve the palate, buccal mucosa, and gingivae. Sometimes, vermilion zone of the lower lip (lupus cheilitis) is also affected [4,5,32]. Ulcers are often aphthous-like with a white to yellow coating and a peripheral red rim especially in the hard palate. A honeycomb plaque is a rare condition, revealed as a chronic, well-defined plaque along with white lacy hyperkeratosis and buccal erythema. The lesions generally affect both lining and masticatory mucosa, however they are less hyperkeratotic on the lining mucosa (e.g., soft palate). Discoid oral lesions appear as whitish steriae generally radiating from the central erythematous area (“brush border” pattern), which makes it difficult to distinguish them from oral candidiasis or OLP if there is no systemic or cutaneous findings. Lupus cheilitis is an inflammatory condition of the lips presenting as a small or diffuse, erythematous and edematous lesion that might develop into crusty painful ulcers. This condition usually affects the vermilion zone of the lower lip. Oral manifestations of CCLE are similar to erosive OLP with an ulcerated or atrophic, erythematous central area and peripheral white, fine, radiating striae. Occasionally the central region shows a fine stippling of white dots along with erythema. However, the oral features are generally accompanied with skin lesions. When ulcerative and atrophic oral lesions come into contact to acidic or salty foods pain might arise similar to erosive OLP. Oral features of SCLE are the same as those of CCLE. Diagnosis of SLE can be quite challenging in primary stages because of its ambiguous clinical course usually with remission phases. American Rheumatism Association has set some clinical and laboratory criteria for the diagnosis of SLE. Occasionally, radiating white striae of oral lesions resemble Wickham’s striae of OLP; Therefore, biopsy is required for definite diagnosis. Mild cases can be successfully managed by means of NSAIDs along with anti-malarial agents. Systemic corticosteroids in combination with other immunosuppressive agents and immunomodulators are frequently used for more severe conditions. Meanwhile, systemic therapy would lead to the amelioration of oral lesions if any (Table 3). Dent. J. Dent. J. 2019, 2019, 7, 7, x15FOR PEER REVIEW 14 14of of 24 24 6. Acquired Lesions That Cannot Be Scraped Off (without Specific Pattern) 6. Acquired Lesions That Cannot Be Scraped Off (without Specific Pattern) 6.1. Frictional Keratosis 6.1. Frictional Keratosis Frictional (traumatic) keratosis is defined as white plaques with a rough and frayed surface Frictional (traumatic) keratosis is of defined as white plaques with a rough frayed surface clearly related to an identifiable source mechanical irritation. These lesions can and occasionally mimic clearly related to an identifiable source of mechanical irritation. These lesions can occasionally mimic dysplastic leukoplakia. The prevalence has been reported as high as 5.5%. This category includes dysplastic Theand prevalence been reported as high as 5.5%. category includes linea alba, leukoplakia. and cheek, lip, tongue has chewing. Traumatic keratosis has This never been shown to linea alba, and cheek, lip, and tongue chewing. Traumatic keratosis has never been shown to undergo malignant changes. Once the irritant is removed the lesion must resolve within twoundergo weeks; malignant changes. the irritant is removed the lesion must resolve within two weeks; otherwise, otherwise, biopsy isOnce mandatory to rule out a dysplastic lesion. biopsy is mandatory to rule out a dysplastic lesion. 6.2. Oral Leukoplakia 6.2. Oral Leukoplakia Oral leukoplakia (OL) has been defined as a white patch or plaque that cannot be attributed to Oral leukoplakia (OL) has been defined as a white patch or plaque that cannot be attributed to any clinically or histologically definite lesion [22,33]. The prevalence of OL is reported 2.6% among any clinically or histologically definite lesion [22,33]. The prevalence of OL is reported 2.6% among general population. Most lesions are seen above the age of 50 with men being more commonly general population. Most lesions are seen above the age of 50 with men being more commonly affected; affected; however, a slight predilection for women has been found in some studies. OL is the however, a slight predilection for women has been found in some studies. OL is the most frequent most frequent potentially malignant lesion of the oral mucosa in a way that 16% to 62% of oral potentially malignant lesion of the oral mucosa in a way that 16% to 62% of oral squamous carcinoma squamous carcinoma are related to a pre-existing leukoplakia. While the etiology of these lesions are related to a pre-existing leukoplakia. While the etiology of these lesions remained unexplained remained unexplained some authors mentioned the relationship between leukoplakia and tobacco, some authors mentioned the relationship between leukoplakia and tobacco, alcohol, sanguinaria, alcohol, sanguinaria, ultraviolet radiation, trauma, betel quid chewing, genetic factors, and ultraviolet radiation, trauma, betel quid chewing, genetic factors, and microorganisms [4,5,33,34]. microorganisms [4,5,33,34]. Clinically, OL manifests as an irreversible, non- scrapable and slightly Clinically, OL manifests as an irreversible, non- scrapable and slightly raised white plaque that raised white plaque that may have a wrinkled, leathery to “dry or cracked-mud” appearance. These may have a wrinkled, leathery to “dry or cracked-mud” appearance. These lesions are divided into lesions are divided into homogenous or non-homogenous types. The homogenous type has a homogenous or non-homogenous types. The homogenous type has a regular, smooth whitish surface regular, smooth whitish surface and well-defined margins. The non-homogenous form of and well-defined margins. The non-homogenous form of leukoplakia consists of an erythematous leukoplakia consists of an erythematous part (erythroleukoplakia or speckled type) or a nodular, part (erythroleukoplakia or speckled type) or a nodular, erosive, ulcerated, or verrucous exophytic erosive, ulcerated, or verrucous exophytic component. In the speckled type the lesion is component. In the speckled type the lesion is predominantly white. The verrucous leukoplakia predominantly white. The verrucous leukoplakia has an elevated, proliferative, or corrugated has an elevated, proliferative, or corrugated surface, and the nodular type develops small polypoid surface, and the nodular type develops small polypoid enlargements or rounded mostly white enlargements or rounded mostly white excrescences [7,22,34] (Figure 8). excrescences [7,22,34] (Figure 8). Figure Figure 8. 8. Leukoplakia Leukoplakia on on the the buccal buccal mucosa. mucosa. Dent. J. 2019, 7, 15 15 of 24 Oral leukoplakia is generally localized or widespread on the buccal mucosa, lip vermilion, and gingivae. Suggested management includes the elimination of predisposing factors, use of beta-carotene, lycopene, ascorbic acid, ↵-Tocopherol (Vitamin E), topical and systemic retinoic acid (Vitamin A), topical bleomycin, cold-knife surgical excision, laser surgery along with regular follow up [3,7,17] (Table 4). Table 4. Characteristics of acquired white lesions that cannot be scraped off, without specific pattern. Entity Age Gender Common Location(s) Clinical Features Treatment Premalignant Frictional keratosis NA NA NA white plaque with rough and frayed surface removal of irritants NA Oral leukoplakia >50 years M buccal mucosa, lip vermilion and gingivae white patch or plaque NA potentially malignant lesion from slight, white vertical bands to thickened, furrowed areas with a shaggy surface systemic anti-herpes virus drugs, topical retinoids or podophyllum resin, combination therapy with acyclovir cream and podophyllumresin, gentian violet, surgical excision or cryotherapy no potential for malignant transformation gingivae non-homogeneous multifocal areas with speckled and rough surface in the form of exophytic, wart-like, verrucous, polypoid projections or erythematous components surgery, carbon dioxide laser ablation, topical photodynamic therapy, oral retinoids, topical bleomycin solution, beta-carotene, methisoprinol (a synthetic antiviral agent), radiation, chemotherapy malignant transformation M floor of the mouth, posterior lateral borders and ventral surface of the tongue red, white, or combined red-and-white lesion; alteration of surface texture into granular, rough, fungating, papillary, and verruciform or crusted lesion; or existence of a mass or irregular ulceration with rolled border and induration on palpation. radiation therapy or combined chemo radiation therapy with or without surgery NA asymptomatic, diffuse, well demarcated, thick white plaque with papillary or verruciform projections NA NA diffuse leathery grayish-white palatal plaque with red points, “dried mud” appearance regression after cessation of smoking not a premalignant condition Premalignant condition OHL PVL OSCC NA mean age: 60 years >65 years M F borders of the tongue unilaterally or bilaterally Verrucous carcinoma elderly M mandibular vestibule, buccal mucosa, gingivae, tongue, and hard palate Nicotinic stomatitis >45 M palate Actinic cheilitis old age M lower lip vermilion dryness, swelling, cracks, atrophic regions, crusting regions, keratotic plaques, chronic ulceration Surgery, cryotherapy, electrosurgery, topical retinoids, 5-flurouracil cream, photodynamic therapy, CO2 laser ablation and vermilionectomy Chronic mucocutaneous candidiasis begins during infancy NA nails, skin, oral and genital mucosae chronic whitish plaques, along with crusts and ulcers antifungal therapy NA NA retro commisures bilaterally, tongue, palate and lips white patches or plaques antifungal therapy, topical retinoids, betacarotene, bleomyin, several surgical techniques NA chronic hyperplastic candidiasis (Candidal leukoplakia) over 50 Dent. J. 2019, 7, 15 16 of 24 6.3. Oral Hairy Leukoplakia Dent. J. 2019, 7, x FOR PEER REVIEW 16 of 24 Oral hairy leukoplakia (OHL) is a white lesion that develops in immunosuppressed patients infected withtowards Epstein-Barr having levels but of CD4 + T lymphocytes. OHLstates is an of indicator of of progress AIDSVirus stageorin HIV low infection, it might occur in other immune progress towards in HIV it might occur in other states of immune deficiencies deficiencies and AIDS verystage rarely in infection, immune but competent individuals [4,5,17,34]. Highly active and very rarely in immune competent individuals [4,5,17,34]. Highly active antiretroviral therapy has antiretroviral therapy has reduced the prevalence of OHL significantly, however, in patients with reduced prevalencerises of OHL significantly, however, in patients with AIDS the men prevalence rises to 80%. AIDS thethe prevalence to 80%. OHL is more commonly observed among with no potential OHL is more commonly observed among men with no potential for malignant transformation [4,17]. for malignant transformation [4,17]. It is clinically described as whitish nonscrapable velvety It is clinically described as whitish nonscrapable plaquesunilaterally that symmetrically involve theshape borders plaques that symmetrically involve the bordersvelvety of the tongue or bilaterally. The of of the tongue unilaterally or bilaterally. The shape of plaques varies from slight, white vertical bands to plaques varies from slight, white vertical bands to thickened, furrowed areas with a shaggy surface thickened, furrowed [5,34,35] (Figure 9). areas with a shaggy surface [5,34,35] (Figure 9). Figure Figure 9. 9. Oral Oral hairy hairy leukoplakia leukoplakia on on the the lateral lateral border border of of the the tongue tongue with with vertical vertical white white folds. folds. OHL OHL infrequently infrequently spread spread to to cover cover the the entire entire dorsal dorsal and and lateral lateral surfaces surfaces of of the the tongue. tongue. Rarely, Rarely, the buccal buccalmucosa, mucosa,soft soft palate, pharynx, or esophagus can be. affected oral hairy palate, pharynx, or esophagus can be affected While. oralWhile hairy leukoplakia leukoplakia is asymptomatic, superimposed infection with candida create symptoms of mild pain is asymptomatic, superimposed infection with candida create symptoms of mild pain and taste and taste alteration [4,35]. Treatment of OHL generally is not needed, and it has been reported to alteration [4,35]. Treatment of OHL generally is not needed, and it has been reported to display display spontaneous regression; however minor discomfort or esthetic concerns may require spontaneous regression; however minor discomfort or esthetic concerns may require therapy. therapy. Therapeutic interventions includeanti-herpes systemic anti-herpes drugs, topical retinoids or Therapeutic interventions include systemic virus drugs,virus topical retinoids or podophyllum podophyllum resin, combination therapy with acyclovir cream and podophyllum resin, gentian resin, combination therapy with acyclovir cream and podophyllum resin, gentian violet, surgical violet, surgical excision, or cryotherapy excision, or cryotherapy [5,35] (Table 4). [5,35] (Table 4). 6.4. Proliferative Proliferative Verrucous Verrucous Leukoplakia Leukoplakia 6.4. Proliferative verrucous verrucous leukoplakia leukoplakia (PVL) (PVL) is is aa different different and and threatening threatening form form of of OL. OL. The The WHO WHO Proliferative has defined it as “a rare but distinctive high-risk clinical form of oral precancerous lesions” [22,36]. has defined it as ‘‘a rare but distinctive high-risk clinical form of oral precancerous lesions” [22,36]. Proliferative verrucous commonly appears in theinelderly women women with no racial Proliferative verrucousleukoplakia leukoplakia commonly appears the elderly with preference. no racial The mean age of patients with long-lasting lesions of PVL was reported over 60 years [4,5,34,37]. preference. The mean age of patients with long-lasting lesions of PVL was reported over 60 years While the While etiology this condition is uncertain geneticgenetic factorsfactors and and viralviral infections such as [4,5,34,37]. the of etiology of this condition is uncertain infections such Human Papilloma Virus especially typetype 16 and and Virus have [36,37]. as Human Papilloma Virus especially 16 18 and 18Epstein-Barr and Epstein-Barr Virusbeen haveproposed been proposed [36,37]. Clinical appearance in the early stage contains small whitish and well-defined patches or plaques appearing as focal and homogeneous keratotic lesions (Figure 10). Dent. J. 2019, 7, 15 17 of 24 Clinical appearance in the early stage contains small whitish and well-defined patches or plaques appearing as focal and homogeneous keratotic lesions (Figure 10). Dent. J. 2019, 7, x FOR PEER REVIEW 17 of 24 Figure 10. Proliferative verrucous leukoplakia spreading over hard palate and alveolar ridges. The lesions enlarge enlarge slowly slowly and and constantly constantly over over time time involving involving diffuse diffuse surfaces surfaces of of the the mucosa. mucosa. The lesions Meanwhile, and rough surface might appear in the Meanwhile, non-homogeneous non-homogeneousmultifocal multifocalareas areaswith withspeckled speckled and rough surface might appear in form of exophytic, wart-like, verrucous, polypoidpolypoid projections or erythematous features [5,34,36,37]. the form of exophytic, wart-like, verrucous, projections or erythematous features PVL usually PVL develops bilaterally, which affects the buccal mucosa, gingivae, and alveolar ridges. [5,34,36,37]. usually develops bilaterally, which affects the buccal mucosa, gingivae, and The gingivae have been reported as the most affected henceaffected a PVL subtype named proliferative alveolar ridges. The gingivae have been reported asarea; the most area; hence a PVL subtype verrucous leukoplakiaverrucous of the gingivae has beenofproposed [22,36,37]. Theproposed rate of malignant transformation named proliferative leukoplakia the gingivae has been [22,36,37]. The rate of for PVL istransformation reported between 63.3% to 100%.between It might63.3% eventually progress develop OSCC or malignant for PVL is reported to 100%. It mighttoeventually progress verrucous Various treatments modalities suchtreatments as surgery, modalities carbon dioxide ablation, to developcarcinoma OSCC or[22,36]. verrucous carcinoma [22,36]. Various suchlaser as surgery, topical retinoids, topical bleomycin solution, beta-carotene, methisoprinol carbon photodynamic dioxide laser therapy, ablation,oral topical photodynamic therapy, oral retinoids, topical bleomycin (a synthetic antiviral agent), radiation, and chemotherapy areagent), suggested. PVL isand a refractory condition solution, beta-carotene, methisoprinol (a synthetic antiviral radiation, chemotherapy are with a recurrence rate of 85%. None of the treatment methods is effective in quiting relapses and suggested. PVL is a refractory condition with a recurrence rate of 85%. None of the treatment malignant and therefore a lifelong follow-uptransformation, is mandatory [36,37]. methods istransformation, effective in quiting relapses and malignant and therefore a lifelong follow-up is mandatory [36,37]. 6.5. Oral Squamous Cell Carcinoma 6.5. Oral OralSquamous squamousCell cellCarcinoma carcinoma (OSCC) comprises 92–95% of all oral cancers. The incidence has been Oral reported highercell among men and patients older than 65 years. Etiology of OSCC is The multifactorial squamous carcinoma (OSCC) comprises 92–95% of all oral cancers. incidence including tobacco smoke, consumption, betelolder quid,than phenol, viral, Etiology bacterial of and fungal has been reported higher alcohol among men and patients 65 years. OSCC is infections, electro-galvanic reaction, radiation, genetics, immunosuppression, expression of oncogenes, multifactorial including tobacco smoke, alcohol consumption, betel quid, phenol, viral, bacterial deactivation of tumor electro-galvanic suppressor genes, malnutrition, iron-deficiency anemia, and someexpression heritable and fungal infections, reaction, radiation, genetics, immunosuppression, conditions [4,5,22]. Oral lesions may present as red, white, or combined red-and-white lesions; of oncogenes, deactivation of tumor suppressor genes, malnutrition, iron-deficiency anemia, and alteration of the surface texture into granular, rough, fungating, papillary, and verruciform crusted some heritable conditions [4,5,22]. Oral lesions may present as red, white, or or combined lesion may be seen; a mass or irregular ulceration with rolled and rough, induration on palpation may red-and-white lesions; alteration of the surface texture intoborder granular, fungating, papillary, also (Figure 11). and exist verruciform or crusted lesion may be seen; a mass or irregular ulceration with rolled border and induration on palpation may also exist (Figure 11). Dent. J. 2019, 7, 15 Dent. J. 2019, 7, x FOR PEER REVIEW 18 of 24 18 of 24 Figure 11.Squamous Squamous Carcinoma with verrucous, plaque like and exophytic clinical Figure 11. CellCell Carcinoma with verrucous, plaque like and exophytic clinical manifestations manifestations at the lateral border of the tongue, extending to the floor of the mouth. at the lateral border of the tongue, extending to the floor of the mouth. The lesion lesion can can be be flat flat or or elevated with some some palpability palpability or or induration. induration. The The Floor Floor of of the the mouth, mouth, The elevated with posterior lateral lateral borders borders and and ventral ventral surface surface of of the the tongue tongue are are considered considered high-risk high-risk areas areas for for OSCC. OSCC. posterior Involvement of of submandibular submandibular and and digastric digastric lymph lymph nodes nodes due due to to cancer Involvement cancer causes causes lymphadenopathy lymphadenopathy with firm which converts to fixed nodes in later stages [4,5].[4,5]. Patients are most often with firmto tohard hardconsistency, consistency, which converts to fixed nodes in later stages Patients are most diagnosed in advanced phasesphases after progression of symptoms related to disease. survival often diagnosed in advanced after progression of symptoms related to Five-year disease. Five-year rate of OSCC 53–56%. 53–56% Treatment planning depends on clinical staging; primary survival rate isofabout OSCC is about. Treatment planning depends ontherefore, clinical staging; stages are primary treated by surgical andsurgical advanced cases and mayadvanced be managed bymay radiation therapyby or therefore, stages are process treated by process cases be managed combinedtherapy chemoradiation therapy with or without surgery 4). surgery (Table 4). radiation or combined chemoradiation therapy with or(Table without 6.6. Verrucous Verrucous Carcinoma Carcinoma 6.6. Verrucous carcinoma tumor, snuff snuff dipper’s dipper’s cancer, cancer, Buschke-Loewenstein Buschke-Loewenstein tumor, tumor, Verrucous carcinoma (Ackerman’s (Ackerman’s tumor, florid oral carcinoma cuniculatum) is aisrare subtype of oral florid oral papillomatosis, papillomatosis,epithelium epitheliumacuniculatum, acuniculatum, carcinoma cuniculatum) a rare subtype of squamous cell carcinoma with distinct clinical and histopathological features [38,39] comprising 2%–9% oral squamous cell carcinoma with distinct clinical and histopathological features [38,39] of all oral carcinomas It iscarcinomas found mostly in It the men over 55. Oralmen verrucous carcinoma comprising 2%–9% of. all oral. is elderly found mostly in the elderly over 55. Oral usually shows slow growth rate, local invasion, and a low tendency to metastasize. However, these verrucous carcinoma usually shows slow growth rate, local invasion, and a low tendency to characteristics depend highly on the size of the tumor and the time of diagnosis [38,39]. Some precursor metastasize. However, these characteristics depend highly on the size of the tumor and the time of lesions such as leukoplakia, erythroplakia, and proliferative verrucous leukoplakia evolve to diagnosis [38,39]. Some precursor lesions such as leukoplakia, erythroplakia, andcan proliferative verrucous carcinoma over time. Its etiology is not well understood, but some causative habits like verrucous leukoplakia can evolve to verrucous carcinoma over time. Its etiology is not well smoking, alcohol consumption, nutlike chewing, and alcohol smokeless tobacco have beennut postulated understood, but some causativebetel habits smoking, consumption, betel chewing,[5,38]. and The role of Human Papilloma Virus in the oncogenesis of verrucous carcinoma has yet to be elucidated. smokeless tobacco have been postulated [5,38]. The role of Human Papilloma Virus in the oncogenesis Verrucous carcinoma manifests diffuse, thick white plaqueaswith of verrucous carcinoma has as yetantoasymptomatic, be elucidated. well-demarcated, Verrucous carcinoma manifests an papillary or verruciform projections on the surface [5,38]. Sometimes the lesion tends to be pink in asymptomatic, diffuse, well-demarcated, thick white plaque with papillary or verruciform coloration due to an inflammatory reaction tothe the lesion tumor.tends All parts oral in mucosa can be affected, projections on the surface [5,38]. Sometimes to beofpink coloration due to an however mandibular vestibule, buccal mucosa, gingivae, tongue, and hard palate are the most involved inflammatory reaction to the tumor. All parts of oral mucosa can be affected, however mandibular sites. In case of tobacco dipping in the maxillary vestibule or are floor ofmost the mouth, these locations vestibule, buccal mucosa, gingivae, tongue, and hard palate the involved sites. In caseare of affected more frequently. tobacco dipping in the maxillary vestibule or floor of the mouth, these locations are affected more A malignant transformation has been related to oral verrucous carcinoma. It comprises less than frequently. 1% toA16% of OSCC with an annual rate of cases per million. It is reported malignant transformation hasincidence been related toone–three oral verrucous carcinoma. It comprises less that the of malignant gingival lesions about 21cases timesper higher than. tongue than 1% rate to 16% of OSCC transformation with an annualinincidence rate of is one–three million It is lesions. considered thetransformation treatment of choice in mostlesions cases; however, combination therapy reported thatSurgery the rateis of malignant in gingival is about 21 times higher than tongue lesions. Surgery is considered the treatment of choice in most cases; however, combination therapy with surgery and radiotherapy is preferred in extensive lesions. The risk of recurrence rises when surgery or radiotherapy is implemented alone [5,38,39] (Table 4). Dent. J. 2019, 7, 15 19 of 24 withJ.surgery and PEER radiotherapy Dent. 2019, 7, x FOR REVIEW is preferred in extensive lesions. The risk of recurrence rises19when of 24 surgery or radiotherapy is implemented alone [5,38,39] (Table 4). 6.7. Nicotinic Stomatitis 6.7. Nicotinic Stomatitis Nicotine stomatitis is a usual white lesion due to smoking, which is also called Nicotine Nicotine stomatitispalate is a usual due to which also called Nicotine Palatines or Palatines or smoker’s [4,5].white This lesion condition is smoking, commonly seenisamong heavy smokers of pipe, smoker’s cigarettes, palate [4,5].and Thisreverse condition is commonly seen heavy of pipe, tobacco, cigarettes, tobacco, smokers as well asamong patients whosmokers drink extremely hot beverages and reverse smokers as well as patients who drink extremely hot beverages habitually. A frequency of habitually. A frequency of 0.1% to 2.5% has been reported with a predilection for men older than 45 0.1% to[4,5,7]. 2.5% has beenboth reported a predilection men older than 45 years [4,5,7].have Albeitsynergistic both high years Albeit highwith temperature and for chemical ingredients of smoke temperature and chemical ingredients of smoke have synergistic effects on developing nicotine stomatitis, effects on developing nicotine stomatitis, the impact of high temperature is much higher than that thechemicals. impact ofNicotine high temperature much higher thanas that chemicals. Nicotine stomatitis primarily of stomatitisisprimarily presents an of erythematous area on the posterior rugae; presents as an erythematous area on the posterior rugae; then the lesion converts to diffuse then the lesion converts to diffuse leathery grayish-white palatal plaque. Red points can leathery also be grayish-white palatalmucosa plaque. that Red points can alsowidened be seen on theswollen white mucosa that actually widened seen on the white are actually and orifices ofare accessory salivary and swollen orifices of accessory salivary glands with periductal nodular keratinization (Figure 12). glands with periductal nodular keratinization (Figure 12). Figure Figure 12. 12. Nicotinic Nicotinic stomatitis stomatitis on on the the hard hard palate. palate. In addition, addition, thickened thickened palatal palatal mucosa mucosa intermingled intermingled with with fissures fissures produce produce aa “dried “dried mud” mud” In appearance. White Whiteplaques plaquesmay mayaffect affectmarginal marginalgingivae gingivaeand andinterdental interdentalpapillae papillaeas aswell well[4,5,7,41]. [4,5,7,41]. appearance. Nicotine stomatitis regress after cessation of smoking and beand replaced with normal Nicotine stomatitiscan canentirely entirely regress after cessation of smoking be replaced with mucosa. normal This is not a premalignant condition; condition; however, reverse smoker’s has apalate considerable potential for mucosa. This is not a premalignant however, reversepalate smoker’s has a considerable potential malignant transformation. anyofwhite lesionmucosa of the palatal mucosathan lasting malignantfor transformation. Therefore, anyTherefore, white lesion the palatal lasting longer one longer aftershould habit be cessation should be carefully to rule out(Table malignancy month than after one habitmonth cessation carefully monitored to rule monitored out malignancy [5,7] 4). [5,7] (Table 4). 6.8. Actinic Cheilitis 6.8. Actinic ActinicCheilitis Cheilitis (AC) is a chronic inflammatory condition also called actinic cheilosis or solar cheilosis [5,42]. The basis is UV light exposure; however other risk factorsor such as Actinic Cheilitis (AC)ofisetiopathogenesis a chronic inflammatory condition also called actinic cheilosis solar old age, fair complexion, immunosuppression, arsenic exposure, and genetic abnormalities are also cheilosis [5,42]. The basis of etiopathogenesis is UV light exposure; however other risk factors such implicated. A significant male predilection with a male to female ratioand of 10:1 might be attributedare to as old age, fair complexion, immunosuppression, arsenic exposure, genetic abnormalities more outdoor occupational activities among men. Therefore, sometimes the terms like “farmers’ lip” also implicated. A significant male predilection with a male to female ratio of 10:1 might be and “lip oftosailors” are used.occupational Primary clinical features are dryness, swelling,sometimes and cracksthe with smooth, attributed more outdoor activities among men. Therefore, terms like blotchy, pale atrophic regions on the lower lip vermilion (95%) [5,22,42]. Moreover, the border between “farmers’ lip” and “lip of sailors” are used. Primary clinical features are dryness, swelling, and vermilion and the adjacent skinpale cannot be easily distinguished. The lesions progress(95%) to rough, scaly, cracks with smooth, blotchy, atrophic regions on the lower lip vermilion [5,22,42]. crusting areas and keratotic plaques on drier of the chronic ulceration Moreover, the border between vermilion and segments the adjacent skinvermilion. cannot beFinally, easily distinguished. The appears, and persists for months and progresses to malignant lesions [5,42]. Some predisposing lesions progress to rough, scaly, crusting areas and keratotic plaques on drier segments of the factors such as immunosuppression tobacco convert and AC to a malignant condition vermilion. Finally, chronic ulcerationand appears, andsmoking persists can for months progresses to malignant lesions [5,42]. Some predisposing factors such as immunosuppression and tobacco smoking can convert AC to a malignant condition (SCC) in 6% to 10% of patients. The warning signs of bleeding, induration, recurrence and sustained pain are suggestive of transforming AC to SCC. Various treatments such as surgery, cryotherapy, electrosurgery, topical retinoids, 5-fluorouracil cream, Dent. J. 2019, 7, 15 20 of 24 (SCC) in 6% to 10% of patients. The warning signs of bleeding, induration, recurrence and sustained pain are suggestive of transforming AC to SCC. Various treatments such as surgery, cryotherapy, electrosurgery, topical retinoids, 5-fluorouracil cream, photodynamic therapy, CO2 laser ablation, and vermilionectomy have been suggested for AC [5,22,42] (Table 4). 6.9. Chronic Mucocutaneous Candidiasis Chronic mucocutaneous candidiasis (CMC) is described as a recurrent or consistent disease involving the nails, skin, oral, and genital mucosa initiated by Candida spp., most frequently C. Albicans. CMC is a rare clinical condition that begins during infancy in 60%–80% of patients, therefore the late onset is uncommon. The etiology is associated with hereditary or acquired T-cell deficits and alteration in the gene responsible for producing cytokine IL-17 that is related to mucosal immunity against Candida Albicans [5,43]. Chronic mucocutaneous candidiasis appears as whitish plaques, along with crusts and ulcers frequently found in the oral and pharyngeal mucosa as well as gastrointestinal and vaginal mucosa. These thick, white plaques of oral lesions generally cannot be scraped off similar to chronic hyperplastic candidiasis, however other clinical forms of candidiasis may appear as well. Various antifungal medications have been suggested for the treatment of oral lesions with some degrees of resistance to antifungal therapy. Imidazole derivatives such as ketoconazole, fluconazole, and itraconazole can be used to manage CMC [5,44]. 6.10. Chronic Hyperplastic Candidiasis (Candidal Leukoplakia) Chronic hyperplastic candidiasis (CHC) also called as candidal leukoplakia, chronic plaque-type and nodular candidiasis is the least common form of oral candidiasis presenting as white patches or plaques which cannot be detached upon scraping and cannot be attributed to any other lesions [4,5,22,45]. Chronic hyperplastic candidiasis constitutes almost 7%–50% of all oral leukoplakias. It is mainly a disease of adulthood with the age range between 31–81 years, and the majority of patients are over 50. Chronic hyperplastic candidiasis is frequently presented as well-demarcated, palpable, raised lesions from small translucent whitish areas to large opaque plaques. If the plaque has a smooth, homogenous white surface, it is called a homogenous leukoplakia. However, the surface often has a fine intermixture of red and white areas resembling a speckled leukoplakia usually possessing a nodular component [5,46]. Chronic hyperplastic candidiasis is typically located on the retro commissure areas bilaterally [4,46]. The tongue, palate, and lips can also be involved [4,5,22,45]. Whether it is simply a candida infection superimposed on a preexisting oral leukoplakia or a newly formed leukoplakia induced by candida species is a matter of debate. An increased risk of malignancy related to CHC has been found as compared to normal mucosa [46,47]. Moreover, a four–five times risk of malignancy has been found in comparison to leukoplakia not associated with candidal infection. Several local or systemic predisposing factors have been identified for CHC such as lack of mucosal integrity, wearing dentures, hyposalivation, acidic and high-glucose-content saliva, tobacco smoking or chewing, diabetes mellitus, immunodeficiency, deficiency of iron and folic acid, high-carbohydrate regimen, and non-secretor status of blood group antigen. Different modalities have been proposed to treat CHC with various success rates such as antifungal therapy, topical application of retinoids, betacarotene, bleomycin, several surgical techniques like cold-knife surgery, laser therapy, and cryosurgery. Many clinicians prefer to treat the lesions with antifungals prior to surgical methods [46,48]. 7. Others Whiteness or pallor of oral mucosa can be seen in some uncommon conditions such as submucous fibrosis, some granulomatous diseases, skin grafts, scar, and uremic stomititis [4,6,19,49,50]. Dent. J. 2019, 7, 15 21 of 24 8. Discussions White lesions of the oral cavity constitute a wide variety of entities with different pathogenesis and clinical features. We proposed a decision tree to classify such lesions according to their clinical manifestations. This helps clinicians to make a more accurate differential diagnoses list. The first major group, congenital non-scrapable white lesions of the oral cavity (Table 1), most commonly appear early in the life with a history of familial involvement [10–12]. When the white plaque fades with stretching leukoedema should be suspected, especially in a smoker patient with the involvement of buccal mucosa [4,11]. On the other hand, diffuse white plaques in the oral cavity along with extraoral mucosal lesions are in accordance with white sponge nevus. Oral white plaques accompanied by conjunctival plaques and eye lesions are usually seen in patients with hereditary benign intraepithelial dyskeratosis. Similarly, dyskeratosis congenita appears as oral white lesions concomitant with nail dystrophy [9,11]. The second major group of oral white lesions is acquired lesions, which can be scraped off (Table 2). Some of the lesions in this category such as mucosal burns, morsicatio, and pseudomembranes of ulcers are due to trauma and can be easily diagnosed by detection of the insulting factor on history taking and clinical examination [4,5,13–15,21]. While pseudomembranous candidiasis in adults and the elderly suggests a systemic or local predisposing factor like debilitating disease or oral microflora imbalance it is quite common in infants and considered somehow normal [4,16]. Noteworthy, scraping a pseudomembrane covering an oral ulcerative lesion will result in a bleeding surface, but in case of candidiasis punctuated bleeding will appear. However, mucosa under derbies has normal appearance. Oral aquired white lesions, which are keratotic and cannot be scraped off are further divided into lesions with specific clinical pattern and those without any specific feature. Because of the profound similarity of keratotic lesions with no clinical pattern, it is mandatory to consider some minor characteristics to differentiate them. The third major group of oral white lesions is white keratotic lesions with a specific pattern (Table 3), which can be differentiated from other entities by their special clinical features like discrete papules, annular or reticular forms; however, they are not distinguishable from each other nor clinically neither microscopically. This group comprises of lichenoid reactions (oral lichen planus, lichenoid contact reaction, drug-induced lichenoid reaction, graft versus host disease) [27–30]. Presence of papules or reticular elements with symmetrical and generalized distribution along with skin or extraoral mucosal (genitalia) involvement would be in favor of lichen planus [4,30]. On the other hand, LCRs usually develop on the mucosa adjacent to a dental restoration or appliance [5,30]. Drug-induced lichenoid reactions (DILRs) are mostly unilateral with a positive history of taking medications capable of inducing such lesions. In addition, resolving of the lesions upon withdrawal of the drug and reappearance or exacerbation by re-challenging confirms the diagnosis of lichenoid drug reaction. Oral GVHD lesions are more widespread than OLP among patients with a past medical history of hematopoietic stem cell transplantation and sometimes with concomitant involvement of other organs such as skin and liver. Another lesion with a clinical specific pattern similar to lichenoid lesions is chronic cutaneous lupus erythematosus (CCLE) with a discoid-patterned lesions comprising of a central ulcerated, atrophic, or erythematous area with white, fine, radiating steriae at the periphery, which is more prominent than OLP and may abruptly terminate with a sharp demarcation. The fourth subgroup of oral white lesions is keratotic lesions that cannot be scraped off without a specific pattern (Table 4). The clinical key for diagnosis of frictional keratosis is accordance of the suspected lesion to the site of chronic mechanical trauma. The traumatic factor can be detected either clinically (e.g., fractured tooth, ill-fit denture, etc.) or through history taking (e.g., self-inflicted trauma) [14,20]. Presence of a keratotic plaque with punctuated interspersed red dots on the palate with a history of smoking or drinking hot beverages are diagnostic for nicotinic stomatitis [4,5,41]. Actinic cheilitis is suspected when white lesions are seen on the lips among patients with a prolonged Dent. J. 2019, 7, 15 22 of 24 history of sun exposure like farmers, fishermen, and other out-doors workers. Chronic hyperplastic candidiasis is considered in patients with underlying disease and simultaneous cutaneous and mucosal candida lesions. A symmetrical white plaque with pigmentation usually with a cracked-mud appearance in the retro commisural area in a smoker patient is suggestive of chronic hyperplastic candidiasis [46–48]. Rapid growth in combination with various clinical features such as ulceration, tissue necrosis, and surface non-homogeneity would prompt the clinician to consider SCC in the upper rankings of differential diagnosis [5,22,40]. Despite SCC, verrucous carcinoma cannot metastatize. It is associated with smokeless tobacco and often exhibits a rough surface [38–40]. Oral leukoplakia is diagnosed when other keratotic white lesions are excluded clinically and histopathologically [33,34]. Proliferative verrucous leukoplakia is suspected when a slowly progressive multifocal leukoplakia with an uneven surface is encountered in a female patient who is not a smoker [36,37]. White vertical bands with a shaggy surface involving borders of the tongue unilaterally or bilaterally in an immunosuppressed patient are characteristic of oral hairy leukoplakia. 9. Conclusions White lesions of the oral cavity include some critical entities that need an organized approach for making the correct diagnosis. In this article, an updated decision tree was proposed in order to help clinicians to make timely differential diagnoses through a stepwise progression method. 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