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 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.) 2 Oral and Maxillofacial Radiology Department, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran; Safi[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 [1]. Oral lesions can be classified into four groups comprising of ulcerations, pigmentations, exophytic lesions, and red-white lesions [2]. 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% [3]. 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 on the Dent. J. 2019, 7, 15 2 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 causedof non-keratotic by fungal material.infections Accordingly,or caustic chemicals, when a clinicianshould be confronts suspected. a white Otherwise, area on white the orallesions mucosa, can bethe attributed first issue to beincreased elucidated thickness is whether of itkeratin can be layer, scraped which off by might means have of a piece been of induced gauze or by not. local If so, frictionala superficial irritation, non-keratotic immunologic layer such reactions, as pseudomembranes, or more crucial most processes commonly such caused as bypremalignant fungal infections or malignantor caustic transformation chemicals, should [4,5]. be suspected. Otherwise, white lesions can be attributed to increased thicknessIn the ofnext keratin step, layer,any specific which mightclinical have pattern been of induced white lesions by local such frictional as papular, irritation, annular, immunologic reticular orreactions, erosive-ulcerative or more crucial patterns, processes or a combination such as premalignant of them (characteristic or malignant transformationfor lichenoid lesions) [4,5]. should be inspectedIn the next in order step, to any differentiate specific clinical whit patterne patterned of white lesions lesions from such non-patterned as papular, ones. annular, reticular or erosive-ulcerativeTherefore, this patterns,narrative or review a combination paper focuses of them on (characteristic three clinicalfor steps lichenoid to approach lesions) oral should white be lesions:inspected The in first order step to differentiateis to determine white whether patterned the lesionslesion is from congenital non-patterned or acquired; ones. the second and third stepsTherefore, are to this inspect narrative if it reviewcan be paper wiped focuses off or on not three and clinical if it has steps a tospecial approach pattern oral or white not. lesions: This diagnosticThe first step process is to determineis presented whether as an updated the lesion clin is congenitalical decision or tree. acquired; A decision the second tree andis a flowchart third steps usedare tofor inspect organizing if it can features be wiped of off lesions or not or and diseases if it has athat special help pattern clinicians or not. make This a diagnosticconstellation process of rationalis presented decisions as an rather updated than clinical haphazard decision ones tree.to reach A decision a conclusive tree is diagnosis a flowchart [1]. used for organizing 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 [1].

2. SearchGeneral Strategy search engines and specialized databases including PubMed, PubMed Central, EBSCO, Science Direct, Scopus, Embase, and authenticated textbooks were used to find relevant topics by meansGeneral of MeSH search keywords engines such and specializedas “mouth databasesdisease,” “oral including keratosis,” PubMed, “oral PubMed leukokeratosis,” Central, EBSCO, and “oralScience leukoplakia”. Direct, Scopus, Related Embase, English-language and authenticated articles textbooks published were from used 2000 to findto 2017 relevant including topics reviews,by means meta-analyses, of MeSH keywords original papers such as (randomized “mouth disease,” or non-randomized “oral keratosis,” clinical “oral trials; leukokeratosis,” prospective orand retrospective “oral leukoplakia”. cohort studies), Related case English-language reports, and case articles series publishedwere reviewed. from 2000Out of to more 2017 includingthan 140 relevantreviews, articles meta-analyses, and textbooks, original five papers textbooks, (randomized and 45 or papers non-randomized were selected clinical including trials; reviews, prospective case or reportsretrospective or case cohort series, studies), and original case reports, articles. and We case described series were 20 reviewed. entities, with Out offocus more on than their 140 clinical relevant aspects.articles andFinally, textbooks, oral white five textbooks,lesions were and 45categorized papers were into selected two major including groups reviews, of congenital case reports and or acquiredcase series, origin and originaland four articles. subgroups: We described those that 20 entities,can be withscrapped focus onoff theiror not, clinical and aspects. patterned Finally, or non-patternoral white lesions lesions were (Figure categorized 1). into two major groups of congenital and acquired origin and four subgroups:Pictures thoseused that in canthis be review scrapped article off or were not, andcollected patterned from or non-patternthe archive lesionsof Oral (Figure Medicine1). DepartmentPictures of used Shahid in this Beheshti review articleDental were School collected under from permission the archive of the of Oral patients Medicine by signing Department the specialof Shahid consent Beheshti form. Dental School under permission of the patients by signing the special consent form.

Figure 1. Figure 1. DecisionDecision tree tree of of oral oral white white lesions. lesions.

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 LeukoedemaLeukoedema is ais commona common normal normal variationvariation of of the the oral oral mucosa. mucosa. The The prevalence prevalence has hasbeen been reportedreported up toup90% to 90% among among blacks blacks and and betweenbetween 10–50% in in whites, whites, with with no nosex sexpredilection predilection [4–6]. [4–6]. HigherHigher prevalence prevalence among among blacks blacks is possibly is possibly due todu moree to mucosalmore mucosal pigmentation pigmentation making making this conditionthis morecondition apparent more [5]. Itapparent is more [5]. distinct It is more in smokers; distinct in however, smokers; after however, smoking after cessation, smoking cessation, it becomes it less obvious.becomes It seems less toobvious. be a developmental It seems to be variationa developmental with an variation unknown with etiology an unknown [4,5]. Clinically etiology it[4,5]. presents as a diffuse,Clinically gray it presents to white, as non-scrapablea diffuse, gray andto white, veil-like non-scrapable condition, and which veil-like can becondition, described which as a can milky be and opalescentdescribed transformation as a milky and of opalescent the oral mucosa. transformation In more of prominent the oral mucosa. cases, In leukoedema more prominent is characterized cases, 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 afterthe gentle manipulation stretching (Figure of the 2). mucosa, which reappears after quitting the manipulation (Figure2).

(A) (B)

FigureFigure 2. Leukoedema: 2. Leukoedema: (A) White(A) White appearance appearance of buccal of buccal mucosa mucosa due todue Leukoedema. to Leukoedema. (B) By (B stretching) By the mucosa,stretching the the white mucosa, wrinkled the whit areae wrinkled disappeared. area disappeared.

LeukoedemaLeukoedema often often involves involves the the buccal buccal mucosa mucosa and sometimes and sometimes the lateral the borders lateral of bordersthe tongue 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 [6]. Leukoedema is asymptomatic with no potential for malignant transformation. No also betreatment affected is required [6]. Leukoedema for this condition is asymptomatic [4,5,7] (Table with 1). no potential for malignant transformation. No treatment is required for this condition [4,5,7] (Table1).

Table 1. Characteristics of congenital/genetically white lesions.

Common Entity Age Gender Clinical Features Treatment Premalignant Location Not Assigned mucosal folds, wrinkled white Leukoedema M = F buccal NA NA (NA) strerias buccal, ventral surface of the symmetrical, thickened, white, tongue, labial corrugated or velvety, diffuse White sponge presents at birth NA mucosa, soft spongy plaques with an NA NA nevus palate, alveolar elevated, irregular and mucosa, floor of fissural surface the mouth bullae formation, erosions, leukoplakic lesions, rapidly bone marrow progressive periodontal transplantation 30% malignant Dyskeratosis buccal, tongue, disease, gingival inflammation 5–12 years NA (BMT), androgens, transformation congenita oropharynx and bleeding, gingival oral and topical in leukoplakia recession, bone loss, decreased vitamin E root/crown ratio, mild taurodontism Hereditary benign opalescent appearance intra epithelial childhood NA buccal, labial mimicking leukoedema/thick, NA NA dyskeratosis corrugated white plaques 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 [2]. WSN is a rare condition with no sex predilection [8]. A prevalence of below one in 200,000 population has been reported [4]. 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] (Table1).

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 [9]. 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] (Table1). 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 [5] (Table1).

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 [13]. 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 [4]. On the other hand, chemical burns can result from the use of chemical materials like topical applications of medications to relieve dental pain (Figure3). Dent. J. 2019, 7, 15 6 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 6 of 24

FigureFigure 3.3. SuperficialSuperficial oral burn due to placement of of an an over-the-counter over-the-counter anaesthetic anaesthetic gel. gel.

SomeSome ofof well-documentedwell-documented caustic materials are are as aspirin,pirin, sodium sodium perborat perborate,e, hydrogen hydrogen peroxide, peroxide, gasoline,gasoline, turpentine,turpentine, rubbingrubbing alcohol, battery acid, isopropyl alcohol, alcohol, phenol, phenol, eugenol, eugenol, carbamide carbamide peroxidase,peroxidase, bisphosphonates,bisphosphonates, chlorpromazine, and and promazine promazine [5,13]. [5,13]. Thermal Thermal burn burn usually usually is is mild mild andand affectsaffects justjust aa smallsmall areaarea asas aa sloughysloughy yellow-white necrotic epithelium epithelium with with areas areas of of erythema erythema andand ulceration ulceration [ 5[5,13,14].,13,14]. However, However, chemical chemical burns burns result result in mucosal in mucosal necrosis necrosis with morewith severemore severe clinical featuresclinical features [13]. In [13]. case In of case short-time of short-time exposure expo tosure chemicals, to chemicals, the superficial the superficial mucosa mucosa becomes becomes white andwhite wrinkled, and wrinkled, but longer but exposures longer exposures lead to denudation lead to ofdenudation the epithelial of the layer epithelial and development layer and of adevelopment yellowish, fibrinopurulent of a yellowish, membranefibrinopurulent over themembra areane [5 ].over Most the cases area of[5]. mucosal Most cases burns of havemucosal little clinicalburns have effects little and clinical improve effects without and treatment improve [wi5,13thout]. Use treatment of rubber [5,13]. dam Use is a preventiveof rubber dam technique is a inpreventive order to technique decrease iatrogenicin order to mucosal decrease burnsiatrogen [5].ic mucosal According burns to the[5]. sizeAccording and symptoms to the size of and the lesions,symptoms some of recommendationsthe lesions, some arerecommendations proposed to manage are proposed these conditions to manage such these as useconditions of non-steroidal such as anti-inflammatoryuse of non-steroidal drugs anti-inflammatory (NSAID’s), antibiotics, drugs antiseptic(NSAID’s), mouthwashes, antibiotics, coverageantiseptic withmouthwashes, a protective emollientcoverage pastewith ora protective a hydroxypropyl emollient cellulose paste film,or a hydroxypropyl topical anesthetics, cellulose and surgical film, topical debridement anesthetics, [5,15 ] (Tableand surgical2). debridement [5,15] (Table 2).

Table 2. Characteristics of acquired white lesions that can be scraped off.

Common Entity Age Gender Clinical Features Treatment Premalignant Location NSAIDs, palatal, posterior sloughy yellow-white necrotic antiseptics, Superficial burn NA NA buccal, anterior epithelium with the areas of NA antibiotics, tongue erythema and ulceration analgesics psuedomembranous buccal, tongue, creamy white plaques, patches, infants/elderly F > M antifungals NA candidiasis palate or papules Pseudomembrane a white, dirty yellow-white or removal of the of oral ulcers and NA NA NA NA grayish-white color debris, oral rinses materia alba shaggy and thickened buccal, lips, lateral macerated gray-white patches cessation the Morsicatio >35 years F > M border of the or plaques with keratin shreds, NA habitual chewing tongue tissue tags or desquamated areas

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

Dent. J. 2019, 7, x FOR PEER REVIEW 7 of 24

Table 2. Characteristics of acquired white lesions that can be scraped off.

Common Entity Age Gender Clinical Features Treatment Premalignant Location palatal, sloughy yellow-white NSAIDs, posterior necrotic epithelium antiseptics, Superficial burn NA NA buccal, with the areas of NA antibiotics, anterior erythema and analgesics tongue ulceration buccal, creamy white psuedomembranous infants/elderly F > M tongue, plaques, patches, or antifungals NA candidiasis palate papules Pseudomembrane of a white, dirty removal of oral ulcers and NA NA NA yellow-white or the debris, NA materia alba grayish-white color oral rinses shaggy and thickened buccal, lips, macerated cessation the lateral gray-white patches or Morsicatio >35 years F > M habitual NA border of plaques with keratin chewing the tongue shreds, tissue tags or desquamated areas

4.2. Pseudomembranous Candidiasis Dent. J. 2019, 7, 15 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% dentateof dentate patients patients and and more more than than 60% 60% of edentulous of edentulous individuals individuals with awith female a female predilection predilection [4]. The [4]. acute The pseudomembranousacute pseudomembranous form of form oral candidiasis of oral candidiasis is usually seenis usually in infants seen due in to theirinfants underdeveloped due to their immuneunderdeveloped system, theimmune elderly system, because the of elderly their compromised because of their immunity compromised and patients immunity on broad-spectrum and patients antibioticson broad-spectrum [4,17] (Figure antibiotics4). [4,17] (Figure 4).

.

FigureFigure 4.4.Pseudomembranous Pseudomembranous candidiasis candidiasis due todue using to broadusing spectrum broad antibiotic;spectrum pseudoantibiotic; membranes pseudo canmembranes be scraped can off be by scraped a piece off of by gauze. a piece of gauze.

ItIt presentspresents as as creamy creamy white white plaques, plaques, patches, patches, or papules or papules that can bethat wiped can offbe with wiped an erythematous off with an anderythematous sometimes and bleeding sometimes area leaving bleeding behind area [4 ,leaving5,17]. The behind classic [4,5,17]. appearance The ofclassic pseudomembranous appearance of candidiasispseudomembranous is called “curdled candidiasis milk” is [ca5].lled Burning “curdled sensation milk” and[5]. Burning foul taste sensation might accompany and foul taste the lesions might asaccompany well [5]. Thethe chroniclesions pseudomembranousas well [5]. The chronic oral candidiasis pseudomembranous is not distinguishable oral candidiasis from its is acute not counterpartdistinguishable that from emerges its acute in patients counterpart with HIV that infection emerges and in thosepatients taking with corticosteroid HIV infection inhalers and those [4]. Thetaking buccal corticosteroid mucosa is frequentlyinhalers [4]. affected The buccal by pseudomembranous mucosa is frequently candidiasis affected by followed pseudomembranous by the tongue andcandidiasis the palate. followed Elimination by the oftongue predisposing and the palate. factors, Elimination if possible, isof thepredisposing cornerstone factors, of treatment if possible, along is withthe cornerstone antifungal regimenof treatment [4] (Table along2). with antifungal regimen [4] (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] (Table2).

4.4. Morsicatio Morsicatio originates from the Latin word morsus, meaning “bite”, which also called morsicatio mucosa oris or chronic mucosal chewing [5]. This lesion is caused by self-induced injury and chronic tissue irritation like habitual chewing of buccal mucosa, chronic nibbling, biting, or sucking (Figure5). Dent. J. 2019, 7, 15 8 of 24

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 [5]. This lesion is caused by self-induced injury and chronic Dent.tissue J. 2019irritation, 7, 15 like habitual chewing of buccal mucosa, chronic nibbling, biting, or sucking (Figure8 of 24 5).

Figure 5. Habitual biting of cheeks and the lower lip.

Most patientspatients denydeny the the self-inflicted self-inflicted injury injury or door itdo subconsciously. it subconsciously. Glass blowersGlass blowers develop develop similar similarchanges changes in their buccalin their mucosa buccal mucosa due to chronic due to irritationchronic irritation as well.The as well. prevalence The prevalence of morsicatio of morsicatio has been hasreported been 0.5%reported to 1.12% 0.5% among to 1.12% the generalamong populationthe general with population a male to with female a male ratio to of female 1/3. This ratio condition of 1/3. Thisis more condition common is in more patients common older thanin patients 35 years, older and than those 35 having years, extra and stress those or having mental extra illness stress [4,5,21 or]. Themental most illness affected [4,5,21]. areas The are most non-keratinized affected areas epithelium are non-keratinized of the buccal epithelium mucosa (morsicatio of the buccal buccarum), mucosa (morsicatiolips (morsicatio buccarum), labiorum), lips and (morsicatio the lateral labiorum), borders of an thed the tongue lateral (morsicatio borders of linguarum), the tongue respectively.(morsicatio linguarum),Morsicatio does respectively. not involve Morsicatio areas not does achievable not in tovolve habitual areas chewing not achievable trauma [to4, 5habitual,14,21]. Whilechewing the traumalesions usually[4,5,14,21]. present While bilaterally the lesions on usually the mid-portion present bilaterally of anterior on buccalthe mid-portion mucosa along of anterior the occlusal buccal mucosaline extensive along lesions the occlusal may involve line largerextensive areas lesion of buccals may mucosa. involve Sometimes larger areas morsicatio of buccal might mucosa. appear Sometimesas unilateral morsicatio lip and/or might tongue appear lesions as unilateral [5]. The clinical lip and/or features tongue include lesions asymptomatic [5]. The clinical shaggy features and includethickened asymptomatic macerated gray-white shaggy and patches thickened or plaques macerate withd gray-white keratin shreds, patches tissue or tags,plaques or desquamated with keratin shreds,areas on tissue the mucosal tags, surface,or desqua whichmated gradually areas on merge the themucosal adjacent surface, mucosa which [4,14,21 gradually]. A peeling merge irregular the adjacentragged surface mucosa with [4,14,21]. erythema A peeling or erosion—but irregular notragged ulceration—might surface with erythema accompany or erosion—but white areas, andnot ulceration—mightthe patient may report accompany the ability white to areas, peel shredsand the of pa thetient white may portionreport the from ability the peripheryto peel shreds of the of thelesions white [4, 5portion,21]. If thefrom clinical the periphery presentation of the of lesions morsicatio [4,5,21]. is typical If the andclinical history presentation taking reveals of morsicatio patients’ ishabit typical of mucosal and history biting thetaking diagnosis reveals will patients’ be established. habit of In mucosal case of any biting doubt, the a biopsydiagnosis seems will to be established.necessary [4 ,5In,21 case]. This of conditionany doubt, has a nobiopsy long-term seems negative to be necessary consequences [4,5,21]. and This generally condition no treatment has no long-termis recommended. negative As consequences morsicatio usually and occursgenerally subconsciously, no treatment the is patients recommended. should give As consultation morsicatio usuallyfor their occurs parafunctional subconsciously, behavior tothe resolve patients it. Nonethelessshould give in consultation some patients for whose their chewing parafunctional 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] (Table2).

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 [4] (Table3). Dent. J. 2019, 7, 15 9 of 24

Table 3. Characteristics of acquired white lesions that cannot be scraped off, with specific pattern.

Common Entity Age Gender Clinical Features Treatment Premalignant Location papular, reticular, plaque-like, bullous, erythematous and topical steroid, potentially middle age, mean posterior buccal ulcerative features; white Lichen planus F > M concurrent use of malignant age of 55 mucosa bilaterally components might be seen as antifungal drugs disorder papules, plaques, and reticular areas restricted to sites that are regularly in contact with same reaction patterns as seen dental materials in OLP, that is, reticulum, replacement of LCR NA F NA such as buccal papules, plaque, erythema, dental materials mucosa and and ulcers lateral borders of the tongue withdrawal of the unilateral with an ulcerative DILR NA NA NA drug and use of NA reaction pattern topical steroids hyperkeratotic reticulations systemic corticosteroids tongue and buccal GVHD NA NA and plaques, erythematous and/or other NA mucosa changes, and ulcerations immunomodulatory agents NSAIDs along ulcerations, erythematous with antimalarial lesions, hyperkeratosis, agents, systemic palate, buccal honeycomb plaque and discoid corticosteroids in SLE mean age: 31 F mucosa, and lesions as whitish steriae combination NA gingivae generally radiating from the with other central erythematous area immunosuppressives (brush border) and immune modulating agents

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 [4]. 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 [17]. 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 (Figure6). Dent. J. 2019, 7, 15 10 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 10 of 24

(A)

(B)

FigureFigure 6. 6.Clinical Clinical features features of of oral oral lichen lichen planus planus with with specific specific white white pattern, pattern, (A) reticular(A) reticular OLP; OLP; the arrow the showsarrow annularshows annular form; (B form;) plaque-like (B) plaque-like OLP. OLP.

Frequently,Frequently, the the striae striae accompany accompany aa surroundingsurrounding erythematouserythematous area. Reticular Reticular OLP OLP often often affects affects thethe posterior posterior buccalbuccal mucosamucosa bilaterally,bilaterally, sometimessometimes the lateral and dorsal tongue, tongue, the the gingiva, gingiva, the the palate,palate, andand infrequentlyinfrequently thethe mucosalmucosal sideside andand vermilionvermilion border of the lips [[4,5,7,22].4,5,7,22]. Plaque-type Plaque-type OLPOLP appears appears asas a a homogeneous homogeneous well-demarcatedwell-demarcated white plaque with peripheral striae. striae. OLP OLP lesions lesions onon thethe dorsumdorsum ofof thethe tonguetongue becomebecome clearclear asas keratotickeratotic white plaques with with glossitis glossitis without without any any striaestriae [4[4,5].,5]. ErythematousErythematous (atrophic), bullous, and and ulcerative ulcerative forms forms of of OLP OLP are are less less common common and and oftenoften surrounded surrounded by by aa whitewhite reticularreticular network.network. SometimesSometimes the erythematous OLP OLP involves involves attached attached gingivaegingivae without without any any papules papules or striae,or striae, which which is called is called desquamative desquamative gingivitis. gingivitis. The reticular, The reticular, papular, andpapular, plaque-like and plaque-like forms of OLP forms commonly of OLP commonly present without present any without symptoms, any symptoms, except for except a brief for roughness. a brief 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% [28]. 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 [29].

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] (Figure7). Dent. J. 2019, 7, 15 12 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 12 of 24

Figure 7. Lichenoid contact reaction in buccal mucosa andand alveolar ridge due to amalgam build-up of 1st and 2nd mandibular molar.

No prevalence raterate hashas been been reported reported for for LCR LCR yet. yet. Women Women are are affected affected more more frequently frequently than than men. men.Clinically, Clinically, LCRs showLCRs theshow same the features same features as seen inas OLP,seen thatin OLP, is, reticulum, that is, reticulum, papules, plaques,papules, erythema, plaques, erythema,and ulcers and [4,5 ].ulcers The most[4,5]. apparentThe most clinical apparent difference clinical betweendifference OLP between and LCR OLP is theand extensionLCR is the of extensionthe lesions. of The the majoritylesions. ofThe LCRs majority are confined of LCRs to ar sitese confined just in contact to sites with just dental in contact materials, with suchdental as materials,the buccal such mucosa as the and buccal the lateral mucosa borders and the of thelateral tongue. borders Lesions of the are tongue. hardly Lesions ever observed are hardly in sitesever observedsuch as the in gingivae,sites such palatalas the gingivae, mucosa, floorpalatal of muco the mouth,sa, floor or of dorsum the mouth, of the or tongue. dorsum Most of the LCRs tongue. are Mostnon-symptomatic, LCRs are non-symptomatic, but the patient but might the experience patient might discomfort experience from discomfort spicy and from hot foodspicy when and hot the foodlesion when converts the tolesion erythematous converts to or erythematous ulcerative forms. or Theulcerative duration forms. of contact The duration with dental of contact material with has dentalthe key material role to develophas the key LCRs role on to the develop oral mucosa. LCRs on Lichenoid the oral mucosa. reactions Lichenoid caused by reactions dental composites caused by dentalhave been composites observed onhave the been mucosal observed side of bothon th uppere mucosal and lower side lips. of Replacementboth upper ofand dental lower materials lips. Replacementin direct contact of dental with LCR materials will result in direct in cure contact or considerable with LCR improvementwill result in incure at leastor considerable 90% of the improvementcases within one in toat twoleast months 90% of [ 4the,5,30 cases]. However, within itone is notto two necessary months to replace[4,5,30]. restorative However, materialsit is not necessarythat are not to inreplace direct restorative contact with materials LCRs. Whilethat are a not malignant in direct potential contact with for LCRs LCRs. has While been a suggested,malignant potentialno prospective for LCRs studies has havebeen beensuggest conducteded, no prospective to support studies this hypothesis have been [4]. conducted to support this hypothesis [4]. 5.5. Drug-Induced Lichenoid Reactions 5.5. Drug-InducedDrug-Induced Lichenoid Lichenoid Reactions Reactions (DILRs) are related to a delayed hypersensitivity reaction. It hasDrug-Induced been suggested Lichenoid that drugs Reactions or their (DILRs) metabolites are related precipitate to a delayed the lichenoid hypersensitivity reaction. reaction. DILRs are It hasuncommon been suggested and account that drugs for a or very their low metaboli percentagetes precipitate of this entitythe lichenoid [4]. There reaction. are many DILRs drugs are uncommonresponsible forand theaccount development for a very of theselow lesionspercentage such of as this non-steroidal entity [4]. anti-inflammatoryThere are many drugs responsibleand angiotensin-converting for the development enzyme of these inhibitors. lesions su Otherch as non-steroidal medications, anti-inflammatory such as anti-malarial drugs and angiotensin-convertingantihypertensive drugs, enzyme diuretics, inhibitors. oral hypoglycemic Other medications, agents, gold salts,such penicillamine,as anti-malarial and betaand antihypertensiveblockers are also relateddrugs, todiuretics, the evolution oral ofhypoglycem DILRs [30].ic DILRs agents, are gold mostly salts, unilateral penicillamine, with an ulcerativeand beta blockerspattern, whichare also might related be quite to the similar evolution to OLP. of UsuallyDILRs [30]. the lesionsDILRs evolveare mostly several unilateral months afterwith thean ulcerativepatient starts pattern, a new which drug. might DILRs be are quite not generally similar to severe; OLP. however,Usually the if alesions patient evolve has serious several symptoms months afterwithdrawal the patient of the starts drug a andnew use drug. of topicalDILRs steroidsare not ge arenerally often recommendedsevere; however, [4]. if a patient has serious symptoms withdrawal of the drug and use of topical steroids are often recommended [4]. 5.6. Graft-Versus-Host Disease (GVHD) 5.6. Graft-Versus-HostGraft-versus-host Disease disease (GVHD) (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 [3]. 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 [31].

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 [5]. 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 [4]. 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 [32]. 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 [4]. 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 [32]. 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 [4]. 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 [5]. Occasionally, radiating white striae of oral lesions resemble Wickham’s striae of OLP; Therefore, biopsy is required for definite diagnosis [32]. 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 [5] (Table3). Dent. J. 2019, 7, x 15 FOR PEER REVIEW 1414 of of 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 clearlyFrictional related to (traumatic) an identifiable keratosis source is of defined mechan asical white irritation. plaques These with lesi aons rough can andoccasionally frayed surface mimic dysplasticclearly related leukoplakia. to an identifiable The prevalence source of has mechanical been reported irritation. as high These as lesions 5.5%. canThis occasionally category includes mimic lineadysplastic alba, leukoplakia.and cheek, lip, The and prevalence tongue haschewing. beenreported Traumatic as highkeratosis as 5.5%. has Thisnever category been shown includes to undergolinea alba, malignant and cheek, changes. lip, and Once tongue the chewing. irritant is Traumatic removed keratosisthe lesion has must never resolve been within shown two to undergo weeks; otherwise,malignant changes.biopsy is Oncemandatory the irritant to rule is removedout a dysplastic the lesion lesion must [6]. resolve within two weeks; otherwise, biopsy is mandatory to rule out a dysplastic lesion [6]. 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 [4]. OL is the however, a slight predilection for women has been found in some studies [4]. 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] (Figure8). excrescences [7,22,34] (Figure 8).

Figure 8. Leukoplakia on the buccal 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, α-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] (Table4).

Table 4. Characteristics of acquired white lesions that cannot be scraped off, without specific pattern.

Common Entity Age Gender Clinical Features Treatment Premalignant Location(s) Frictional white plaque with rough and removal of NA NA NA NA keratosis frayed surface irritants buccal mucosa, lip potentially Oral leukoplakia >50 years M vermilion and white patch or plaque NA malignant lesion gingivae systemic anti-herpes virus drugs, topical retinoids or podophyllum borders of the from slight, white vertical resin, combination no potential for tongue OHL NA M bands to thickened, furrowed therapy with malignant unilaterally or areas with a shaggy surface acyclovir cream transformation bilaterally and podophyllumresin, gentian violet, surgical excision or cryotherapy surgery, carbon dioxide laser ablation, topical photodynamic non-homogeneous multifocal therapy, oral areas with speckled and rough retinoids, topical mean age: 60 surface in the form of malignant PVL F gingivae bleomycin years exophytic, wart-like, verrucous, transformation solution, polypoid projections or beta-carotene, erythematous components methisoprinol (a synthetic antiviral agent), radiation, chemotherapy red, white, or combined red-and-white lesion; alteration floor of the mouth, of surface texture into granular, radiation therapy posterior lateral rough, fungating, papillary, or combined OSCC >65 years M borders and and verruciform or crusted chemo radiation NA ventral surface of lesion; or existence of a mass or therapy with or the tongue irregular ulceration with rolled without surgery border and induration on palpation. mandibular asymptomatic, diffuse, well vestibule, buccal Verrucous demarcated, thick white plaque elderly M mucosa, gingivae, NA NA carcinoma with papillary or verruciform tongue, and hard projections palate diffuse leathery grayish-white regression after not a Nicotinic >45 M palate palatal plaque with red points, cessation of premalignant stomatitis “dried mud” appearance smoking condition Surgery, cryotherapy, electrosurgery, dryness, swelling, cracks, topical retinoids, lower lip atrophic regions, crusting 5-flurouracil Premalignant Actinic cheilitis old age M vermilion regions, keratotic plaques, cream, condition chronic ulceration photodynamic therapy, CO2 laser ablation and vermilionectomy Chronic nails, skin, oral begins during chronic whitish plaques, along mucocutaneous NA and genital antifungal therapy NA infancy with crusts and ulcers candidiasis mucosae antifungal therapy, chronic topical retinoids, hyperplastic retro commisures betacarotene, candidiasis over 50 NA bilaterally, tongue, white patches or plaques NA bleomyin, several (Candidal palate and lips surgical leukoplakia) techniques 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 ofinfected progress with towards Epstein-Barr AIDS Virus stage or in having HIV lowinfection, levels but of CD4 it might + T lymphocytes. occur in other OHL states is an of indicator immune of deficienciesprogress towards and AIDSvery stage rarely in HIVin infection,immune butcompetent it might occurindividuals in other states[4,5,17,34]. of immune Highly deficiencies active antiretroviraland very rarely therapy in immune has reduced competent the individuals prevalence [ 4of,5 ,OHL17,34 ].significantly, Highly active however, antiretroviral in patients therapy with has AIDSreduced the the prevalence prevalence rises of OHL to 80%. significantly, OHL is more however, commonly in patients observed with AIDS among the men prevalence with no rises potential to 80%. forOHL malignant is more commonly transformation observed [4,17]. among It is men clinically with no described potential foras malignantwhitish nonscrapable transformation velvety [4,17]. plaquesIt is clinically that symmetrically described as whitish involve nonscrapable the borders velvetyof the tongue plaques unilaterally that symmetrically or bilaterally. involve The the shape borders of plaquesof the tongue varies unilaterally from slight, or white bilaterally. vertical The bands shape to of thickened, plaques varies furrowed from slight,areas whitewith a vertical shaggy bands surface to [5,34,35]thickened, (Figure furrowed 9). areas with a shaggy surface [5,34,35] (Figure9).

FigureFigure 9. 9. OralOral hairy hairy leukoplakia leukoplakia on on the the lateral lateral border border of the tongue with vertical white folds.

OHL infrequently spread spread to to cover cover the the entire dors dorsalal and and lateral lateral surfaces surfaces of of the the tongue. tongue. Rarely, Rarely, thethe buccalbuccal mucosa, mucosa, soft soft palate, palate, pharynx, pharynx, or esophagus or esophagus can be affectedcan be [affected5]. While [5]. oral While hairy leukoplakiaoral hairy leukoplakiais asymptomatic, is asymptomatic, superimposed superimposed infection with infection candida with create candida symptoms create symptoms of mild pain of mild and tastepain andalteration taste alteration [4,35]. Treatment [4,35]. Treatment of OHL generallyof OHL generally is not needed, is not needed, and it has and been it has reported been reported to display to displayspontaneous spontaneous regression; regression; however however minor discomfortminor discomfort or esthetic or esthetic concerns concerns may require may therapy.require therapy.Therapeutic Therapeutic interventions intervention include systemics include anti-herpes systemic anti-herpes virus drugs, virus topical drugs, retinoids topical or podophyllum retinoids or podophyllumresin, combination resin, therapy combination with acyclovirtherapy with cream acyclovir and podophyllum cream and resin,podophyllum gentian violet,resin, surgicalgentian violet,excision, surgical or cryotherapy excision, or [5, 35cryotherapy] (Table4). [5,35] (Table 4).

6.4. Proliferative Proliferative Verrucous Verrucous Leukoplakia Proliferative verrucous leukoplakia (PVL) is a different and threatening form of OL. The WHO has defined it it as as ‘‘a “a rare but distinctive distinctive high-risk high-risk clinical clinical form form of of oral oral precancerous precancerous lesions” lesions” [22,36]. [22,36]. Proliferative verrucousverrucous leukoplakia leukoplakia commonly commonly appears appears in the in elderly the elderly women women with no racialwith preference.no racial preference.The mean ageThe ofmean patients age of with patients long-lasting with long-las lesionsting of PVLlesions was of reported PVL was over reported 60 years over [ 460,5, 34years,37]. [4,5,34,37].While the While etiology the ofetiology this condition of this condition is uncertain is uncertain genetic genetic factors factors and and viral viral infections infections such such as asHuman Human Papilloma Papilloma Virus Virusespecially especially type type 16 and 16 18and and 18Epstein-Barr and Epstein-Barr Virus haveVirus beenhave proposed been proposed [36,37]. [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 spreadin spreadingg over hard palate and alveolar ridges.

The lesions enlarge slowly and constantly over time involving diffuse surfaces surfaces of of the the mucosa. mucosa. Meanwhile, non-homogeneousnon-homogeneous multifocalmultifocal areas areas with with speckled speckled and and rough rough surface surface might might appear appear in the in formthe form of exophytic, of exophytic, wart-like, wart-like, verrucous, verrucous, polypoid po projectionslypoid projections or erythematous or erythematous features [5 ,34features,36,37]. PVL[5,34,36,37]. usually PVL develops usually bilaterally, develops which bilaterally, affects thewhich buccal affects mucosa, the buccal gingivae, mucosa, and alveolargingivae, ridges. and Thealveolar gingivae ridges. have The been gingivae reported have as thebeen most reported affected as area;the most hence affected a PVLsubtype area; hence named a PVL proliferative subtype verrucousnamed proliferative leukoplakia verrucous of the gingivae leukop haslakia been of proposed the gingivae [22,36 has,37 ].been The pr rateoposed of malignant [22,36,37] transformation. The rate of formalignant PVL is transformation reported between for PVL 63.3% is reported to 100%. between It might 63.3% eventually to 100%. progress It might to eventually develop OSCCprogress or verrucousto develop carcinoma OSCC or [ 22verrucous,36]. Various carcinoma treatments [22,36]. modalities Various such treatments as surgery, modalit carbon dioxideies such laser as surgery, ablation, topicalcarbon photodynamicdioxide laser therapy,ablation, oral topical retinoids, photodynam topical bleomycinic therapy, solution, oral retinoids, beta-carotene, topical methisoprinol bleomycin (asolution, synthetic beta-carotene, antiviral agent), methisoprinol radiation, and(a synthetic chemotherapy antiviral are agent), suggested. radiation, PVL is and a refractory chemotherapy condition are withsuggested. a recurrence PVL is ratea refractory of 85%. Nonecondition of the with treatment a recurrence methods rate is effectiveof 85%. inNone quiting of the relapses treatment and malignantmethods is transformation, effective in quiting and therefore relapses a lifelongand malignant follow-up transformation, is mandatory [36 and,37]. therefore a lifelong follow-up is mandatory [36,37]. 6.5. Oral Squamous Cell Carcinoma 6.5. OralOral Squamous squamous Cell cell Carcinoma carcinoma (OSCC) comprises 92–95% of all oral cancers [22]. The incidence has beenOral reported squamous higher cell among carcinoma men and (OSCC) patients comprises older than 92–95% 65 years. of all Etiology oral cancers of OSCC [22]. is The multifactorial incidence includinghas been reported tobacco smoke,higher alcoholamong men consumption, and patients betel older quid, than phenol, 65 years. viral, Etiology bacterial of and OSCC fungal is infections,multifactorial electro-galvanic including tobacco reaction, smoke, radiation, alcohol genetics, consumption, immunosuppression, betel quid, expressionphenol, viral, of oncogenes, bacterial deactivationand fungal infections, of tumor electro-galvanic suppressor genes, reaction, malnutrition, radiation, iron-deficiency genetics, immunosuppression, anemia, and some expression heritable conditionsof oncogenes, [4, 5deactivation,22]. Oral lesions of tumor may suppressor present as genes, red, white, malnutrition, or combined iron-deficiency red-and-white anemia, lesions; and alterationsome heritable of the surfaceconditions texture [4,5,22]. into granular, Oral lesions rough, fungating,may present papillary, as red, and verruciformwhite, or orcombined crusted lesionred-and-white may be seen; lesions; a mass alteration or irregular of the ulceration surface texture with rolled into border granular, and rough, induration fungating, on palpation papillary, may alsoand existverruciform (Figure 11or). 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 18 of 24 Dent. J. 2019, 7, x FOR PEER REVIEW 18 of 24

Figure 11.11.Squamous Squamous Cell Cell Carcinoma Carcinoma with verrucous,with verrucous, plaque like plaque and exophytic like and clinical exophytic manifestations clinical manifestationsat the lateral border at the of lateral the tongue, border extending of the tongue, to the extending floor of the to mouth.the floor of the mouth.

The lesion can be flat flat or elevated with some pa palpabilitylpability or induration. The The Floor Floor of of the the mouth, mouth, posterior lateral borders and ventral surface surface of of th thee tongue tongue are are considered considered high-risk high-risk areas areas for for OSCC. OSCC. Involvement of of submandibular and and digastric lymp lymphh nodes due to cancer causes lymphadenopathy with firmfirm toto hard hard consistency, consistency, which which converts converts to fixedto fixed nodes nodes in later in late stagesr stages [4,5]. [4,5]. Patients Patients are most are most often oftendiagnosed diagnosed in advanced in advanced phases phases after progression after progressi of symptomson of symptoms related torelated disease. to Five-yeardisease. Five-year survival survivalrate of OSCC rate isof about OSCC 53–56% is about [22]. 53–56% Treatment [22]. planning Treatment depends planning on clinical depends staging; on therefore, clinical staging; primary therefore,stages are primary treated by stages surgical are processtreated by and surgical advanced process cases and may advanced be managed cases by may radiation be managed therapy by or radiationcombined therapy chemoradiation or combined therapy chemoradiation with or without therapy surgery with [5 or] (Table without4). surgery [5] (Table 4).

6.6. Verrucous Verrucous Carcinoma Verrucous carcinoma (Ackerman’s tumor, snuff dipper’s cancer, cancer, Buschke-Loewenstein Buschke-Loewenstein tumor, tumor, florid oraloral papillomatosis,papillomatosis, epithelium epithelium acuniculatum, acuniculatum, carcinoma carcinoma cuniculatum) cuniculatum) is ais rare a rare subtype subtype of oral of oralsquamous squamous cell carcinoma cell carcinoma with distinct with clinical distinct and histopathologicalclinical and histopathological features [38,39] comprisingfeatures 2%–9%[38,39] comprisingof all oral carcinomas 2%–9% of [all40]. oral It is carcinomas found mostly [40]. in It the is elderlyfound mostly men over in the 55 [elderly5]. Oral men verrucous over 55 carcinoma [5]. Oral verrucoususually shows carcinoma slow growth usually rate, shows local invasion,slow growth and arate, low tendencylocal invasion, to metastasize. and a low However, tendency these to metastasize.characteristics However, depend highly these oncharacteristics the size of the depend tumor andhighly the on time the of size diagnosis of the [tumor38,39]. and Some the precursor time of diagnosislesions such [38,39]. as leukoplakia, Some precursor erythroplakia, lesions such and proliferativeas leukoplakia, verrucous erythroplakia, leukoplakia and canproliferative evolve to verrucous carcinomaleukoplakia over can time evolve [38]. to Its verrucous etiology is carcinoma not well understood, over time but[38]. some Its etiology causative is habits not well like understood,smoking, alcohol but some consumption, causative betel habits nut like chewing, smokin andg, alcohol smokeless consumption, tobacco have betel been nut postulated chewing, [5 and,38]. smokelessThe role of Humantobacco Papilloma have been Virus postulatedin the oncogenesis [5,38]. The of role verrucous of Human carcinoma Papilloma has Virus yet to in be the elucidated oncogenesis [38]. ofVerrucous verrucous carcinoma carcinoma manifests has asyet an to asymptomatic, be elucidated diffuse, [38]. well-demarcated,Verrucous carcinoma thick whitemanifests plaque as with an asymptomatic,papillary or verruciform diffuse, projectionswell-demarcated, on the surfacethick white [5,38]. plaque Sometimes with the papillary lesion tends or toverruciform be pink in projectionscoloration dueon the to an surface inflammatory [5,38]. Sometimes reaction to the the lesion tumor. tends All partsto be of pink oral in mucosa coloration can bedue affected, to an inflammatoryhowever mandibular reaction vestibule, to the tumor. buccal All mucosa, parts gingivae,of oral mucosa tongue, can and be hard affected, palate however are the most mandibular involved vestibule,sites. In case buccal of tobacco mucosa, dipping gingivae, in thetongue, maxillary and hard vestibule palate or are floor the of most the mouth, involved these sites. locations In case are of tobaccoaffected dipping more frequently in the maxillary [5]. vestibule or floor of the mouth, these locations are affected more frequentlyA malignant [5]. transformation has been related to oral verrucous carcinoma. It comprises less than 1% toA 16%malignant of OSCC transformation with an annual has incidence been related rate ofto one–threeoral verrucous cases percarcinoma. million [It1 ].comprises It is reported less thanthat the1% rateto 16% of malignant of OSCC transformationwith an annual in incidence gingival lesionsrate of isone–three about 21 cases times per higher million than [1]. tongue It is reportedlesions [38 that]. Surgery the rate is of considered malignant the transformation treatment of choice in gingival in most lesions cases; however,is about 21 combination times higher therapy than tongue lesions [38]. 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

Dent.with J. surgery2019, 7, x FOR and PEER radiotherapy REVIEW is preferred in extensive lesions. The risk of recurrence rises19 when of 24 surgery or radiotherapy is implemented alone [5,38,39] (Table4). 6.7. Nicotinic Stomatitis 6.7. Nicotinic Stomatitis Nicotine stomatitis is a usual white lesion due to smoking, which is also called Nicotine PalatinesNicotine or smoker’s stomatitis palate is a usual [4,5]. white This lesioncondit dueion tois smoking,commonly which seen is among also called heavy Nicotine smokers Palatines of pipe, or tobacco,smoker’s cigarettes, palate [4,5 ].and This reverse condition smokers is commonly as well seen as amongpatients heavy who smokers drink extremely of pipe, tobacco, hot beverages cigarettes, habitually.and reverse A smokers frequency as wellof 0.1% as patients to 2.5% whohas been drink reported extremely with hot a beverages predilection habitually. for men A older frequency than 45 of years0.1% to[4,5,7]. 2.5% hasAlbeit been both reported high with temperature a predilection and forchemical men older ingredients than 45 years of smoke [4,5,7]. have Albeit synergistic both high effectstemperature on developing and chemical nicotine ingredients stomatitis, of smoke the haveimpact synergistic of high temperature effects on developing is much nicotine higher stomatitis,than that ofthe chemicals. impact of Nicotine high temperature stomatitis is primarily much higher presents than as that an oferythematous chemicals. Nicotine area on the stomatitis posterior primarily rugae; thenpresents the aslesion an erythematous converts to diffuse area on leathery the posterior grayish-white rugae; then palatal the lesion plaque. converts Red points to diffuse can leatheryalso be seengrayish-white on the white palatal mucosa plaque. that Red pointsare actually can also widened be seen onand the swollen white mucosa orifices that of are accessory actually widenedsalivary glandsand swollen with periductal orifices of accessorynodular keratinization salivary glands (Figure with periductal 12). nodular keratinization (Figure 12).

FigureFigure 12. 12. NicotinicNicotinic stomatitis stomatitis on on the the hard hard palate.

InIn addition, addition, thickened thickened palatal palatal mucosa mucosa intermin intermingledgled with with fissures fissures produce produce a a “dried “dried mud” mud” appearance.appearance. White White plaques plaques may may affect affect marginal marginal gingivae gingivae and and interdental interdental papillae papillae as as well well [4,5,7,41]. [4,5,7,41]. NicotineNicotine stomatitisstomatitis cancan entirely entirely regress regress after after cessation cessation of smoking of smoking and beand replaced be replaced with normal with mucosa.normal mucosa.This is not This a premalignant is not a premalignant condition; condition; however, reversehowever, smoker’s reverse palate smoker’s has a palate considerable has a considerable potential for potentialmalignant for transformation. malignant transformation. Therefore, any Therefore, white lesion any of white the palatal lesion mucosa of the palatal lasting longermucosa than lasting one longermonth than after one habit month cessation after should habit becessation carefully should monitored be carefully to rule monitored out malignancy to rule [5 ,7out] (Table malignancy4). [5,7] (Table 4). 6.8. Actinic Cheilitis 6.8. ActinicActinic Cheilitis Cheilitis (AC) is a chronic inflammatory condition also called actinic cheilosis or solar cheilosisActinic [5,42 Cheilitis]. The basis (AC) of is etiopathogenesis a chronic inflammatory is UV light condition exposure; also however called actinic other risk cheilosis factors or such solar as cheilosisold age, fair[5,42]. complexion, The basis immunosuppression,of etiopathogenesis is arsenicUV light exposure, exposure; and however genetic other abnormalities risk factors are such also asimplicated. old age, fair A significant complexion, male immunosuppression, predilection with a malearsenic to femaleexposure, ratio and of 10:1genetic might abnormalities be attributed are to alsomore implicated. outdoor occupational A significant activities male amongpredilection men. Therefore,with a male sometimes to female the termsratio of like 10:1 “farmers’ might lip”be attributedand “lip of to sailors” more outdoor are used. occupational Primary clinical activiti featureses among are dryness,men. Therefore, swelling, sometimes and cracks the with terms smooth, like “farmers’blotchy, pale lip” atrophic and “lip regions of sailors” on the lowerare used lip. vermilion Primary (95%)clinical [5 ,features22,42]. Moreover, are dryness, the border swelling, between and cracksvermilion with and smooth, the adjacent blotchy, skin pale cannot atrophic be easily regions distinguished. on the lower The lesionslip vermilion progress (95%) to rough, [5,22,42]. scaly, Moreover,crusting areas the border and keratotic between plaques vermilion on drier and segmentsthe adjacent of theskin vermilion. cannot be Finally,easily distinguished. chronic ulceration The lesionsappears, progress and persists to rough, for months scaly, crusting and progresses areas and to malignantkeratotic plaques lesions [on5,42 drier]. Some segments predisposing of the vermilion.factors such Finally, as immunosuppression chronic ulceration and appears, tobacco and smoking persists canfor months convert and AC toprogresses a malignant to malignant condition 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] (Table4).

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 [43]. CMC is a rare clinical condition that begins during infancy in 60%–80% of patients, therefore the late onset is uncommon [44]. 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 [44]. 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 [4]. 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 [46]. It is mainly a disease of adulthood with the age range between 31–81 years, and the majority of patients are over 50 [46]. 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 [46]. 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 [5]. 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 [22]. 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 [46]. 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 (Table1), 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 [8]. Oral white plaques accompanied by conjunctival plaques and eye lesions are usually seen in patients with hereditary benign intraepithelial dyskeratosis [13]. 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 (Table2). 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 [4]. 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 (Table3), 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 [30]. 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 [31]. 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 [32]. The fourth subgroup of oral white lesions is keratotic lesions that cannot be scraped off without a specific pattern (Table4). 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 [42]. 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 [35].

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.

Author Contributions: conceptualization, H.M.; methodology, H.M.; data collection, H.M., M.B., S.J; writing—original draft preparation, S.J., F.A., S.R., Y.S.; writing—review and editing, M.B. and F.A.; visualization, and supervision, H.M., and M.B.; project administration, H.M. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflicts of interest.

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