White and Red Lesions of the Oral Mucosa€¦ · White and Red Lesions of the Oral Mucosa Maryam...

White and Red Lesions of the OralMucosa

Maryam Jessri, Hani Mawardi, Camile S. Farah, andSook-Bin Woo

AbstractThere are several conditions that can present aswhite or red macular, papular, and/or plaque-like lesions of the oral mucosa. Based on etiol-ogy, red and white lesions of the oral cavity canbe divided into developmental, reactive, infec-tious, immune-mediated/autoimmune, and

potentially malignant and malignant conditions.Whiteness of the oral mucosa can be caused bychanges in the epithelium such as keratinizationof normally nonkeratinized mucosa (such as thebuccal mucosa), increased keratinization of nor-mally keratinized mucosa, abnormal keratiniza-tion of the epithelium, thickening of theepithelium, and epithelial edema. Fibrosisand/or reduced vascularity of the underlyingmucosa may also lead to whiteness whichtends to appear deep without discernible surfacealterations. Some of the more common causesof redness (erythema) of the oral mucosainclude reduced keratinization of the oral epi-thelium, epithelial atrophy, erosion or inflam-mation, and vascular dilatation or proliferation.Generally, the prevalence of red and white orallesions increases with age. Based on diagnosticand inclusion criteria and characteristics of thepopulation, prevalence of oral mucosal lesionshas been reported in 2–84% of the population(Do et al. 2014). A large proportion of red andwhite lesions are benign. However, the mostcommon premalignant condition in the oral cav-ity is a white plaque (leukoplakia), and this mustbe managed expeditiously and appropriately.Many conditions can be accurately diagnosedwith careful history taking and clinical exami-nation. However, a biopsy is often necessary fora definitive diagnosis. This chapter discusses theclinical features of these white and red lesions,how to distinguish between them, and how tomanage them.

M. JessriDivision of Oral Medicine and Dentistry, Brigham andWomen’s Hospital, Boston, MA, USA

Department of Oral Medicine, Infection and Immunity,Harvard School of Dental Medicine, Boston, MA, USA

School of Dentistry and Oral Health Centre of WesternAustralia, University of Western Australia, Perth, WA,Australiae-mail: [email protected]; [email protected]

H. MawardiFaculty of Dentistry, King Abdulaziz university, Jeddah,Saudi Arabia

Division of Oral Medicine and Dentistry, Brigham andWomen’s Hospital, Boston, MA, USAe-mail: [email protected]

C.S. Farah (*)School of Dentistry and Oral Health Centre of WesternAustralia, University of Western Australia, Perth, WA,Australiae-mail: [email protected]

S.-B. WooDivision of Oral Medicine and Dentistry, Brigham andWomen’s Hospital, Boston, MA, USA

Department of Oral Medicine, Infection and Immunity,Harvard School of Dental Medicine, Boston, MA, USAe-mail: [email protected]; [email protected]

# Springer International Publishing AG 2017C.S. Farah et al. (eds.), Contemporary Oral Medicine,DOI 10.1007/978-3-319-28100-1_16-1

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mailto:[email protected]






KeywordsWhite lesions • Red lesions • Premalignantlesions •Mucosal pathology • Benign mucosalpathology • Developmental conditions • Reac-tive conditions • Potentially malignant lesions •Malignant lesions • Oral squamous cellcarcinoma

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Developmental Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . 2Fordyce Granules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2White Sponge Nevus (Cannon White Sponge Nevus,

Familial White Folded Dysplasia) . . . . . . . . . . . . . . . . 3Hereditary Benign Intraepithelial Dyskeratosis

(Witkop Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Reactive Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Chemical Desquamation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Leukoedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Smokeless Tobacco Keratosis . . . . . . . . . . . . . . . . . . . . . . . . . 5Morsicatio Mucosae Oris (Chronic Bite

Keratosis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Benign Alveolar Ridge Keratosis . . . . . . . . . . . . . . . . . . . . . 8Contact Stomatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Nicotinic Stomatitis (Stomatitis Nicotina) . . . . . . . . . . . . 11Hairy/Coated Tongue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Candidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Oral Hairy Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Immune-Mediated and AutoimmuneConditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Benign Migratory Glossitis (Geographic Tongue,Erythema Areata Migrans, MigratoryStomatitis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Desquamative Gingivitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Plasma Cell Gingivostomatitis (Plasma Cell Orificial

Mucositis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Oral Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Oral Graft Versus Host Disease . . . . . . . . . . . . . . . . . . . . . . . 23Erythema Multiforme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Precancerous and Cancerous Lesions . . . . . . . . . . . . . . 26Leukoplakia and Proliferative Verrucous

Leukoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Erythroplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Oral Submucous Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Actinic Cheilitis (Actinic Cheilosis, Solar Cheilosis,

and Farmer’s Lip) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Oral Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . 35

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . 36

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Introduction

This chapter focuses on red and white macular,papular, and plaque lesions of the oral mucosa.There are many conditions in this chapter whichoverlap with entities discussed in other chapters.For instance, oral lichen planus and lichenoidlesions will only be discussed briefly here asthere is a full-length chapter elsewhere in thistextbook dedicated specifically to this topic. Like-wise, the topic of oral candidosis is covered ingreat detail in the chapter on Oral Fungal Infec-tions, and malignant lesions are covered in thechapter on Oral Mucosal Malignancies. The con-ditions described in this chapter are divided byetiology as follows:

• Developmental conditions• Reactive conditions• Infections• Immune-mediated and autoimmune conditions• Potentially malignant and malignant lesions

Developmental Conditions

Fordyce Granules

Fordyce granules are benign sebaceous glandscommonly found in the oral cavity that have ahigh prevalence of up to 80%, and as such theyare generally considered to be a normal variationof the oral mucosa. However, their density andprevalence are reportedly higher in individualswith hyperlipidemia and Muir-Torre syndrome(Ponti et al. 2015).

Etiology and PathophysiologyFordyce granules are a variation of the normal oralphenotype. However, because of increased prev-alence around puberty, as well as with increase inage, some authors suggest hormonal influence intheir etiopathogenesis although it is more likelythat they become fully expressed when patientsreach adulthood (Choudhry et al. 1992).

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Clinical-Pathologic FeaturesFordyce granules are seen in 80% of the generaladult population with no particular gender predi-lection. They present as multiple asymptomatic,yellow or yellowish-white, 1–3 mm macules andpapules, most commonly seen on the buccalmucosa, and vermilion of the upper lip. They aregenerally bilateral and symmetrically distributed(Fig. 1). Occasionally, some of the sebaceousglands may become hyperplastic and papular(up to 3–5 mm in size) so that the patient or oralhealth care provider may become more awareof them.

Patient ManagementFordyce granules require no treatment other thanrecognition of the condition and reassurance ofthe patient. A biopsy is not usually requiredbecause of their typical appearance and distribu-tion. Sebaceous hyperplasia is not uncommon, butsebaceous adenoma is rare (Izutsu et al. 2003).

White Sponge Nevus (Cannon WhiteSponge Nevus, Familial White FoldedDysplasia)

White sponge nevus is a rare autosomal dominantdisorder with highly variable expressivity thataffects the oral and other mucosae but not the skin.

Etiology and PathophysiologyWhite sponge nevus is caused bymutation in genesassociated with keratin-4 (KRT4) or keratin-13(KRT13) resulting in keratin instability and abnor-mal aggregation of tonofilaments which in turnpromotes abnormal proliferation and thickeningof the oral epithelium (Rugg et al. 1995; Shibuyaet al. 2003).

Clinical-Pathologic FeaturesThe lesions of white sponge nevus appear at birth,early childhood, or adolescence and usually pre-sent in a bilateral, symmetric fashion as asymp-tomatic, thick, white, spongy plaques, usually onthe buccal mucosa, ventral tongue, lip mucosa,and soft palate (Songu et al. 2012). There mayalso be esophageal, upper airway, and genitallesions, but the skin is not affected.

Diagnosis is established through a biopsybecause other conditions such as chronic trau-matic keratoses may appear clinically similar.

Patient ManagementPatients should be reassured that this is a benigninherited condition that will persist throughoutlife. There is no effective treatment. Cases thathave reportedly responded to antibiotics or anti-bacterial mouth rinses are not likely to representthis condition but instead a reactive keratosis.

Fig. 1 Fordyce granules.Yellow papules on the leftbuccal mucosa

White and Red Lesions of the Oral Mucosa 3

Hereditary Benign IntraepithelialDyskeratosis (Witkop Disease)

Hereditary benign intraepithelial dyskeratosis(HBID) is a rare autosomal dominant disorderpresenting with bulbar conjunctival and oralplaques. It was first identified in 1960 and pre-dominantly affects descendants of Haliwa-SaponiNative Americans in North Carolina (Cummingset al. 2008).

Etiology and PathophysiologyRecent haplotype analysis of families with HBIDshowed a possible role of duplication of chromo-some 4q35, which may trigger uncontrolled cellproliferation and premature keratinization of theepithelium (Allingham et al. 2001).

Clinical-Pathologic FeaturesHBID manifests at birth or early childhood withno gender predilection. Oral lesions are generallyasymptomatic and present as non-tender, spongy,white plaques on the buccal mucosa, lips, ventralsurface of the tongue, and floor of the mouth,usually in a bilateral fashion. Ocular lesions pre-sent as white-gray gelatinous plaques on the bul-bar conjunctiva, and these may be asymptomatic,or patients may experience irritation, frequent lac-rimation, a feeling of a foreign body in the eye,and photophobia. Corneal vascularization maylead to blindness in rare cases. One unusual fea-ture of HBID is worsening of symptoms in springand summer.

A biopsy is usually required to confirm thediagnosis and rule out other conditions such aswhite sponge nevus or even frictional keratosis.

Patient ManagementPatients should be reassured that HBID is a benigninherited condition that will persist throughoutlife. There is no effective treatment.

Reactive Lesions

Chemical Desquamation

Superficial chemical desquamation of oralmucosa occurs in response to exposure to chemi-cal irritants present in mouth rinses and tooth-pastes, and it is also referred to as oralepitheliolysis. Harsher chemicals such as aspirinor other chemicals used in dentistry such as meth-acrylate cause more coagulations, erosions, andulcers (irritant contact stomatitis) because of sub-stantial inflammation and should be differentiatedfrom superficial chemical desquamation.

Etiology and PathophysiologyChemical desquamation is induced by variousirritants including, but not limited to, mouth-washes with high-alcohol content (such asListerine

®

(Johnson and Johnson, NJ, USA) andPro-Health

®

(Crest, Procter & Gamble Co., OH,USA) and strongly flavored toothpastes(Francalanci et al. 2000). Such caustic dentifricescan lead to coagulation and detachment of themost superficial 2–3 layers of epithelial cellswhich slough off yet leave behind intact thinnerepithelium. In vitro studies have shown desqua-mation of human oral mucosa within 24 hrs fol-lowing exposure to dentifrice resulting in aninflammatory response characterized byupregulation of IL-1β, downregulation of IL-8,and TNF-α secretion (Mostefaoui et al. 2002).

Clinical-Pathologic FeaturesChemical desquamation is more common inadults because they tend to use dental productsthat have stronger additives. It presents as pain-less, wispy, gray-white threads, and membranousmaterial that can be easily peeled off or spontane-ously slough, leaving behind normal mucosa(Fig. 2). Chronic exposure may be associatedwith leukoedema or cheilitis.

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Patient ManagementLesions resolve on ceasing or changing theoffending toothpaste or mouth rinse to a versionwithout the offending chemical.

Leukoedema

Leukoedema, in its primary form, is commonenough to be considered a variation of normal,with some studies reporting a prevalence of up to90% especially in dark-skinned patients becauseof the color contrast between the milky-whiteleukoedema on darker mucosa.

Etiology and PathophysiologyLeukoedema is the clinical term, while the patho-logic process is keratinocyte edema. It is the result offluid accumulation within keratinocytes, a processcaused by mild local irritation, such as from ciga-rette or marijuana smoking, the use of some tooth-pastes and mouth rinses, and from physical traumasuch as sucking (Heyl and Raubenheimer 1987). Itis often seen at the periphery of contact desquama-tions or even frictional or factitial keratosis.

Clinical-Pathologic FeaturesLeukoedema is a condition of adults; however, ithas been reported as early as 2 years of age insome patients and transiently in the sucking padsof infants (Madani and Kuperstein 2014). Its

prevalence differs between gender and racialgroups ranging from 0.96% to 90% of the popu-lation with the highest prevalence in African-American males (Madani and Kuperstein 2014;Pinto et al. 2014). Leukoedema presents asasymptomatic, white-gray translucent linearreticulations, most frequently seen on the buccalmucosa and to a lesser extent, the lip mucosa andventral tongue.

The complete disappearance of these palereticulations upon stretching the mucosa (theso-called “stretch test”) is a diagnostic feature(Fig. 3a, b). A biopsy is rarely necessary althoughthe reticulations may be mistaken for those oflichen planus, prompting a biopsy.

Patient ManagementStretching the mucosa and the disappearance ofreticulations distinguish leukoedema from reticularlichen planuswhich is a keratotic lesion. The patientshould be reassured as to the benign nature of thecondition. If there is an associated smoking habit, itis a good opportunity to discuss habit cessation.

Smokeless Tobacco Keratosis

Smokeless tobacco (ST) keratosis describes oralchanges caused by prolonged contact of themucosa to ST products. This includes chewing

Fig. 2 Chemicaldesquamation from a mouthrinse: sloughing of thesuperficial layers ofepithelium leaving behindnormal-looking mucosa


tobacco which takes several forms: loose leaf orshredded tobacco that may be sweetened and fla-vored, tobacco plug that also may be sweetenedand sold as a compacted brick, or twist tobaccothat is composed of tobacco leaves twisted into arope from which sections can be bitten or cut off.Another common product is snuff composed offinely or coarsely ground, dry (that can beinhaled), or moist powdered tobacco (that is“dipped”) and sold loose or in prepackagedsachets. Dissolvable tobacco tablets are also avail-able. While the consumption rate of ST hasremained stable among American women (1 inevery 100), following a transient decreasebetween 1986 and 2000, ST is regaining popular-ity among American males (7 in every 100) (U.S2014). In the 1980s, STwas thought to be stronglyassociated with the development of squamous cellcarcinoma (Winn et al. 1981); however morerecent studies have shown a low association(Rodu and Cole 2002).

Etiology and PathophysiologyST keratosis in its early stage is a form of contactirritation that develops at the site where thetobacco product is placed. Cessation of the habitleads to complete restoration of mucosa to itsnormal appearance. However, prolonged expo-sure for years may lead to the development ofcontact irritation lesion which is generally notreversible. Moist ST products with high alkalinityare more strongly associated with the develop-ment of contact irritation lesions.

Although the term “keratosis” is convention-ally used to describe this lesion, most ST lesionsshow predominantly edema of superficial epithe-lial cells often with only very focal or even noparakeratin formation. This is why many lesionsresolve within days of habit cessation, especiallyin earlier stages of the condition. However, whenleathery white plaques develop within these gray-ish edematous plaques after years or decades ofuse, the term leukoplakia could be applied despiteits known etiology.

Clinical-Pathologic FeaturesThe habit of using ST is particularly commonamong younger males (starting between 8 and14 years of age) in many populations worldwideincluding North America, Northern Europe, andAsian countries. Early lesions appear as asymp-tomatic, soft, gray-white, poorly demarcated,edematous changes of the mucosa with parallelridges, at the site of tobacco placement; lesions arenot usually indurated or ulcerated (Fig. 4a, b).Common sites are the mandibular and maxillaryvestibules. These lesions resolve within days toweeks of habit cessation. However, the use of STat one site over years and decades may result inthe development of well-demarcated, leathery,and often fissured white plaques of leukoplakiawhich will generally not resolve on discontinua-tion of the habit. Other oral changes associatedwith ST use include gingival recession, periodon-tal disease, caries, and occlusal wear (Kamathet al. 2014).

Fig. 3 Leukoedema of right buccal mucosa. (a) Diffuse, filmy, slightly reticulated area on the right buccal mucosa.(b) Stretching the mucosa causes the lesion to disappear

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A biopsy is usually unnecessary but will showedema of superficial epithelial cells (similar tothose seen in leukoedema) because of contactinjury, while the mid- and lower epithelial cellsare normal. However, once a leukoplakia has beenestablished, the lesions should be biopsied to eval-uate for dysplasia.

Patient ManagementMost ST lesions are readily diagnosed based onthe history and clinical examination. The earlygray-white and ridged lesions resolve with habitcessation within days to a few weeks. The densewhite lesions of leukoplakia that develop afteryears of use generally do not resolve on habitcessation and have the potential for dysplasiaand carcinoma similar to other leukoplakias.Pooled analysis of previous studies showed STlesions have a weak association with oral cancer(OR = 1.81, 95% CI: 1.04, 3.17) compared withconventional cigarette smoking (Wyss et al.2016).

Morsicatio Mucosae Oris (Chronic BiteKeratosis)

Morsicatio mucosae oris (MMO) or chronic bite/frictional keratosis is a benign, trauma-inducedlesion of the oral mucosa. MMO must be differ-entiated from leukoplakia which has malignantpotential.

Etiology and PathophysiologyAs opposed to acute bite trauma which usuallypresents as an ulcer, MMO is caused by chronictrauma to the nonkeratinized mucosa that is usu-ally associated with parafunctional habits,whether conscious or unconscious. This leads toparakeratosis and benign epithelial hyperplasia.This includes nibbling or sucking on the mucosa,as well as rubbing of the mucosa against dentalprostheses or other hardware such as orthodonticbraces and piercings. Similar lesions have beenreported in the oral mucosa of the glassblowers(Schiodt et al. 1980). Its counterpart on thekeratinized mucosa is benign alveolar ridge kera-tosis (see later).

Clinical-Pathologic FeaturesMMO is usually seen in individuals over the ageof 35 and peaks in the fifth and sixth decades oflife with a higher predilection for females (Wooand Lin 2009). The most common sites are thebuccal mucosa (often appearing as an extension oraccentuation of linea alba), the lateral/ventraltongue, and the lower lip mucosa. Most MMOlesions are bilateral, and more than half of patientsdo not report a history of such habits, or the habitsmay be nocturnal. The majority of cases present asasymptomatic, poorly demarcated, thickened,shaggy, white ragged papules and plaques thatmay be associated with focal areas of erythemaor ulceration (Fig. 5a–c). Often times, patients

Fig. 4 (a) Early smokeless tobacco lesion after 6 days ofuse: fissured, poorly demarcated slightly gray-white lesionof the lower lip and vestibule; there is no significant

keratosis. (b) Smokeless tobacco lesion showing poorlydemarcated parallel pale gray-white ridges and folds in thevestibule (Courtesy of Dr. Jeffrey Stone, Lowell, MA, USA)


report being able to remove desquamated wisps oftissue from the surface of the lesion.

A biopsy will exhibit histopathologic findingsof reactive keratosis.

Patient ManagementMMO is a benign lesion, and patients should bereassured that these are reactive lesions usuallycaused by a parafunctional habit, whether con-scious, unconscious, or nocturnal, with no malig-nant potential. However, all patients should havean examination of the muscles of mastication.Muscle tenderness suggests a clenching orbruxing habit with the potential for developingtemporomandibular joint myofascial pain syn-drome, and fabricating a night guard may beappropriate. However, using a habit-breakingdevice purely for managing MMO has not gener-ally been successful in eradicating the lesions.Such devices themselves may cause the same

frictional keratosis if the patient continues thehabit and macerates the mucosa against thedevice.

Benign Alveolar Ridge Keratosis

Benign alveolar ridge keratosis (BARK) is abenign frictional/traumatic hyperkeratosis onkeratinized alveolar ridge mucosa or the palatalmucosa (Natarajan and Woo 2008). Historically,BARK may have been classified under oral leu-koplakia which implies potential for malignanttransformation (Waldron and Shafer 1975; Napieret al. 2003). However, BARK is a distinct histo-pathologic and clinical entity that should be dif-ferentiated from other white keratinized lesions ofthe oral cavity and most importantly distinguishedfrom leukoplakia because it has no malignantpotential (Woo et al. 2014). It should also be

Fig. 5 Morsicatio mucosa oris (all images are from asingle patient). (a) Poorly demarcated linear plaque alongthe bite line of the tongue. (b) Poorly demarcated red and

white plaque along the linea alba region, with fading mar-gins. (c) Poorly demarcated white papules and plaques ofthe right lower lip mucosa and contiguous buccal mucosa

8 M. Jessri et al.

differentiated from “alveolar ridge keratosis”which is not a specific histopathologic entity, butrather any keratotic lesion on the ridge, frictional,dysplastic, or cancerous (Chi et al. 2007).

Etiology and PathophysiologyBARK is a benign, reactive lesion which resultsfrommechanical trauma, likely from food crushedagainst the edentulous alveolar ridge mucosa. Theoral mucosa responds with deposition of keratinand benign epithelial hyperplasia. It is the oralcounterpart of the skin lesion, lichen simplexchronicus, a frictional/factitial keratosis, thatshares similar histopathologic features.

Clinical-Pathologic FeaturesBARK is noted during the fifth to seventh decadesof life, and males are more commonly affected(Natarajan and Woo 2008). It presents as anasymptomatic poorly demarcated white plaque,most commonly seen on the mandibularretromolar pad (often bilaterally), but also on theedentulous maxillary or mandibular alveolar ridgemucosa (Fig. 6a, b). The surface of a BARK lesionis often rough and slightly verrucous, which raisesthe specter of verrucous leukoplakia.

A biopsy may be performed on suspiciouslesions to establish the diagnosis, and the histo-pathologic features are specific.

Patient ManagementBARK is a benign lesion without potential formalignant transformation, and no treatment isrequired. Due to similarity in clinical presentation,BARK should be differentiated from leukoplakiawhich is a clinical entity that has malignantpotential.

Contact Stomatitis

Lesions of contact stomatitis are red and/or whitethat are located where a known contactant hasbeen placed. It can be divided into twomain types:

(a) Irritant contact stomatitis resulting fromdirect injury to the mucosa from an irritatingsubstance placed against the mucosa, but withmore damage than simple chemicaldesquamation

(b) Allergic contact stomatitis or contact hyper-sensitivity reaction resulting from hypersensi-tivity to a component of the contactant

A systemic hypersensitivity reaction to otheragents such as foods or flavoring agents (such asphenolic compounds) is a different entity that mayresult in the swelling of the lip such as is seen inorofacial granulomatosis which is discussedelsewhere.

Fig. 6 Benign alveolar ridge keratosis: poorly demarcated white plaque of the (a) right retromolar pad and(b) left retromolar pad


Etiology and PathophysiologyIrritant contact stomatitis develops due to expo-sure of oral mucosa to a local chemical irritantthat, depending on causticity, may lead to variableclinical findings. Long-standing contact with anirritant results in coagulation of the surface epi-thelial cells such as seen in smokeless tobaccolesions. More caustic agents such as aspirin, ordental materials such as methacrylate, lead toinflammation, erosion, and ulceration.

Allergic contact stomatitis or contact hyper-sensitivity reaction develops as a result of a typeIV hypersensitivity reaction to a contactant suchas cinnamic aldehyde or peppermint in dentifricesand candies or mercury in amalgam restorations(Isaac-Renton et al. 2015).

Clinical-Pathologic FeaturesIrritant contact stomatitis is generally seen inadults because the pediatric population is unlikelyto use strongly flavored dentifrices or smokelesstobacco or be involved in complex dental proce-dures. Mild irritant contact stomatitis may onlyresult in patients sensing or observing a change inthe color or texture of the mucosa, and patients maynot seek care for this condition. An example is theasymptomatic, wrinkled, white lesions seen insmokeless tobacco use or reactive keratosis causedby mouthwash (Fig. 7a, b). For more caustic sub-stances such as aspirin or methacrylate, changesdevelop within minutes to hours of contact.

Erythema develops at the site of placementfollowed by variable gray-white changes fromedema and coagulation of the epithelium and,depending on the length of exposure and strengthof the contactant, painful ulceration (Spencer et al.2016). This is usually easily diagnosed by taking agood history and correlating this with the clinicalpresentation; therefore a biopsy is not usuallynecessary.

Allergic contact stomatitis or contact hyper-sensitivity reaction occurs in areas where there isdirect contact with the offending agent, such asmucosal contact with amalgam, candies, orchewing gum. The area has a red and/or whitemacule or reticulated area that is poorly demar-cated and that is usually sensitive or painful;ulcers may be present. One form of contact hyper-sensitivity reaction presents as desquamative gin-givitis where the gingiva is diffusely bright red. Abiopsy shows sheets of polyclonal plasma cells,and as such this condition is known as plasma cellgingivitis.

In most cases, the diagnosis is readily arrived atbecause of the location and appearance of thelesion together with the history of contact withan offending agent. Removal of the offendingcontactant (such as replacing an amalgam with acomposite restoration) may lead to resolution ofthe lesion. If in doubt, a biopsy should beperformed to rule out other conditions such as

Fig. 7 Contact stomatitis: (a) Diffuse, white translucentchange of the ventral tongue in a female patient with10–15-year history of rinsing with 10% carbamide perox-ide mouthwash. (b) Ventral tongue of the same patient,

showing complete resolution of the lesion, 40 days afterdiscontinuation of rinsing with 10% carbamide peroxidemouthwash

10 M. Jessri et al.

erythroleukoplakia. Contact hypersensitivityreactions may be lichenoid on histopathology.

Patient ManagementIrritant contact stomatitis: For chronic exposureto other mildly caustic substances, the lesions willresolve completely upon discontinuation of use ofthose products. If this is acute and caused byplacement of aspirin or exposure to more causticdental materials, topical steroid therapy (such asfluocinonide 0.05% gel or betamethasonedipropionate 0.05% ointment) may help to pro-mote healing.

Allergic contact stomatitis or contact hyper-sensitivity reaction: Once the biopsy has con-firmed/established the nature of this lesion,removal of the contactant (such as amalgam) orcessation of the habit (such as eating candies orchewing gum) is a definitive therapy (Woo 2012).Topical steroids help resolve lesions morequickly, and topical anesthetics such as benzo-caine help to ease pain. If the biopsy showsplasma cell stomatitis, patch testing may be help-ful to identify the specific allergen.

Nicotinic Stomatitis (StomatitisNicotina)

Nicotinic stomatitis (NS) is an inflammatory con-dition of the hard palatal mucosa presenting asthickened and hyperkeratotic alteration of the pal-atal mucosa, commonly seen with pipe, cigar, orreverse smokers (Ramulu et al. 1973). Reverse

smoking lesions which are the most severe formof nicotinic stomatitis have been classified by theWHO as an oral potentially malignant condition(Warnakulasuriya et al. 2007).

Etiology and PathophysiologyNS is a misnomer because the lesions develop inresponse to the intense heat associated withsmoking habits and not from nicotine. It is partic-ularly prominent in reverse smokers because theheat from placing the lit end of the cigarette in themouth is intense; this is a practice that is notinfrequent in India and some Southeast Asiancommunities. It has also been reported in patientswho habitually consume extremely hot beverages.As a result of chronic exposure to heat, the palatalmucosa becomes hyperkeratotic and thickened,and the orifices of excretory salivary ductsbecome inflamed.

Clinical-Pathologic FeaturesNS is more common in males in the fifth decadeand older and is usually asymptomatic. The pala-tal mucosa is diffusedly whitened, and establishedlesions are fissured, with a cobblestone or “driedmud” appearance. The surface often containsscattered 1–3 mm, red punctuate papules that rep-resent the inflamed orifices of minor salivarygland ducts (Fig. 8). Because these lesions arefairly uniform appearing and symmetric, anylocalized area that appears raised, warty, or fleshymust be viewed with suspicion and biopsied.

Fig. 8 Nicotinic stomatitis:diffuse whiteness of thepalatal mucosa withcobblestone appearance andred puncta (Courtesy ofDr. Ivan Stojanov, CaseWestern ReserveUniversity, Cleveland,Ohio, USA)


Patient ManagementEarly NS lesions may regress on cessation of pipesmoking; however, patients with persistentlesions should be followed up regularly to monitorfor malignant transformation, particularly reversesmokers (Saunders 1958; Alvarez Gomez et al.2008; van der Eb et al. 1993).

Hairy/Coated Tongue

Hairy tongue (HT) is an acquired benign oralcondition characterized by marked elongation offiliform papillae resulting in a hairlike appearanceor a matted/coated appearance of the tonguedorsum.

Etiology and PathophysiologyHT is caused by retention or accumulation ofkeratin on the filiform papillae and/reduced nor-mal desquamation; the first is usually caused bydehydration and the second by poor diet (Manabeet al. 1999). In the first circumstance, patientshave dry mouths where their salivary glands areproducing less watery and more sticky, mucus-containing viscid saliva so that keratin is retained.This is most frequently seen in patients who havesalivary gland hyposalivation from taking

anticholinergic medications, not drinking suffi-cient water, or with chronic anxiety or as a resultof smoking tobacco. Less frequent causes ofhyposalivation include head and neck radiationfor cancer and Sjogren’s syndrome. In the secondcircumstance, there is reduced mechanical des-quamation of the keratin on the filiform papillaein individuals who consume mostly soft, pro-cessed foods and insufficient coarse foods suchas fresh fruits and vegetables. This includes hos-pitalized patients, patients who are very ill, andthose with poor diet. These lesions may be mis-diagnosed as candidosis because of the whitenessof the tongue and because cultures may be posi-tive for candida although that may merely repre-sent normal oral carriage.

Clinical-Pathologic FeaturesHT is generally seen in adults because it isstrongly associated with hyposalivation andchronic illness, and there may be a male predilec-tion. It is usually asymptomatic and generallyaffects the anterior two-third of the tongue dor-sum, sparing the lateral borders and the tip(Fig. 9a, b). These matted papillae may be stainedby the natural color of foods, food dyes, tobacco,or pigment produced by pigment-producingbacteriae (chromogenic) on the tongue. Common

Fig. 9 Hairy tongue. (a) Elongated yellow brown filiform papillae of themid- and posterior dorsal tongue. (b) Two-monthfollow-up of the same patient after improving hydration and chewing fresh pineapple

12 M. Jessri et al.

colors are brown, yellow, or black (hence, the termblack HT). Prolonged contact with bismuth sub-salicylate, an antacid, may also discolor thetongue dorsum (Gurvits and Tan 2014).

Some patients report halitosis, dysgeusia,and/or a stale or metallic taste, symptoms thatare often associated with a dry mouth (Gurvitsand Tan 2014). The matted, hairy texture maycause gagging. If burning is present, the patientshould be evaluated for oral candidosis whichmay look similar but will usually involve sitesother than the tongue and does not usually havea diffuse, symmetric appearance on the tonguedorsum alone. This is particularly important inpatients who are on antibiotics where it is impor-tant to distinguish between dehydration and/orpoor oral intake from illness and the presentationassociated with oral candidosis.

Patient ManagementHT is self-limiting with no serious sequelae, andpatients should be reassured that they do not havean infection. Improved hydration, eating a dietcontaining fresh fruits and vegetables, and reduc-ing habits that cause dehydration of the mucosa(such as smoking and using alcoholic mouthrinses) will improve this condition. Brushing thetongue gently with a soft toothbrush or gentle useof a tongue scraper helps to remove the retainedkeratin and promote desquamation, but should beused sparingly so as not to cause further irritationto the dorsal tongue epithelium. Anecdotal evi-dence suggests that eating acidic and fibrous foodssuch as pineapple may also reduce keratin reten-tion, while brushing the tongue with dilutedsodium hypochlorite solution can also beeffective.

Infections

Candidosis

Candidosis is the most common fungal infectionin the mouth.

Etiology and PathophysiologyOral candidosis is most commonly caused byCandida albicans. This organism can be isolatedfrom the oral cavity of 30–50% of the asymptom-atic dentate population; this prevalence likelyincreases with age. This merely indicates carriage,and hence a positive carriage culture in theabsence of clinical manifestations should not beinterpreted as representative of an active infection(Tejani et al. 2016). Predisposing factors forcandidosis include (a) alterations in the local envi-ronment, such as hyposalivation and use of topicalsteroids; (b) alterations in the systemic environ-ment, such as use of systemic antibiotics andimmunosuppressive agents; diabetes mellitus;hematinic deficiencies; intrinsic immunodefi-ciency syndromes or acquired immunodeficiencysuch as HIV/AIDS; and 3) positive candidal car-riage. Other members of the Candida genus thatcan affect the oral cavity includeC. guilliermondii, C. tropicalis, C. dubliniensis,C. krusei, and C. parapsilosis; however, they areless common in the general population and aremore frequently seen in patients with HIV/AIDS.

Clinical-Pathologic FeaturesCandidosis occurs across a broad age rangedepending on clinical circumstances as outlinedabove. Patients may be asymptomatic but moreoften present with sensitivity and a burning sen-sation, or even pain, and sometimes dysgeusia(Sharon and Fazel 2010). Several clinical mani-festations exist as follows:

Pseudomembranous candidosis or thrush:This presents as white, curdy papules and plaquescomposed of tangled hyphae, yeast, and desqua-mated epithelial cells (Fig. 10a). These adherentpapules and plaques may or may not be scrapedoff the mucosal surface leaving behind erythema-tous, often bleeding mucosa. Pseudomembranouscandidosis often occurs after antibiotic therapy orhigh-dose steroid therapy in susceptible individ-uals and is common in those with HIV/AIDS(Reichart et al. 2000). When lesions are presentdiffusely on the tongue dorsum, they auto-inoculate the palatal mucosa, and these arereferred to as “kissing lesions.”


Erythematous candidosis: As the nameimplies, it presents as erythematous,raw-appearing lesions of the oral mucosa andhas been further subclassified based on the clinicalpresentation, anatomical site, or etiology asfollows:

• Denture stomatitis or chronic atrophiccandidosis characterized by sensitive or pain-ful, well-delineated erythema limited to thedenture-bearing areas, more commonly seenon the palatal mucosa (Fig. 10b).

• Median rhomboid glossitis or central papillaryatrophy of the midline of the dorsum of thetongue characterized by an often ovoid areaof depapillation and erythema just anterior tothe foramen cecum (Fig. 10c).

• Angular cheilitis characterized by painful ery-thema and fissuring of the corners of the mouth(Fig. 10d). Reduced vertical dimension leadsto dampness and maceration predisposing tocandidal growth in this particular form ofcandidosis. This is often exacerbated by pre-existing iron or vitamin B12 deficiency. Thisform of candidosis is often associated withconcomitant infection with Staphylococcusaureus (Ohman et al. 1986; Smith et al. 2003).

Hyperplastic candidosis: It presents as asymp-tomatic white plaques that cannot be scraped off.It is more common in the anterior buccal mucosaand lateral tongue. Hyperplastic candidosis maybe associated with endocrinopathies and hairyleukoplakia.

Fig. 10 (a) Pseudomembranous candidosis: whiteplaques and papules and erythema involving the hard andsoft palate. (b) Erythematous candidosis: erythema of thepalatal mucosa beneath a denture. (c) Median rhomboid

glossitis and angular cheilitis in an edentulous after antibi-otic therapy. (d) Angular cheilitis: erythematous, macer-ated areas at the commissures

14 M. Jessri et al.

The diagnosis is usually established by theclinical appearance of the lesion or by identifyinghyphae through a scrape and potassium hydroxidepreparation or by cytologic examination. Abiopsy is not usually necessary, but if performed,hyphae are readily identified.

Patient ManagementTopical and systemic antifungal medications arediscussed elsewhere, including management ofprostheses which act as fomites. In brief, topicaltherapy includes nystatin rinses and pastilles, clo-trimazole and miconazole troches, and, in somecountries, topical amphotericin. Combinations ofantifungal agents and a topical steroid (such asnystatin and triamcinolone or clotrimazole andbetamethasone) are useful for atrophic candidiasisrelated to dentures and for angular cheilitis. Treat-ment of concomitant Staphylococcus infections iswith topical erythromycin. Systemic therapyincludes fluconazole.

Patients with recalcitrant disease should beevaluated for systemic disease such as diabetesmellitus or even HIV/AIDS. In patients treatedwith long-term systemic steroids or with recurrentinfection episodes, prophylaxis regimens shouldbe considered. Drug resistance to fluconazole maydevelop in patients on long-term antifungal ther-apy, and other agents include voriconazole,itraconazole, posaconazole, and echinocandins.

Oral Hairy Leukoplakia

Oral hairy leukoplakia (OHL) is a benign condi-tion of the tongue caused by Epstein-Barr virus(EBV) and is most frequently seen in immuno-compromised patients such as those withHIV/AIDS as well as in patients on immunosup-pressive therapy such as organ transplant recipi-ents (Bhayat et al. 2010). However, OHL has alsobeen reported in immunocompetent individuals(Greenspan et al. 2016).

Etiology and PathophysiologyOHL is caused by EBV infection within the muco-sal epithelium, and biopsies show the presence of

EBV-encoded RNAwithin the nuclei of epithelialcells. The current theory or etiopathogenesis sug-gests initial infection of basal epithelial cells withEBV followed by replication of EBV in the epi-thelial cells and B cells (Slots et al. 2006). Circu-lating cytotoxic T cells function to maintain alatent state of the virus during this process. Inimmunocompromised and immunosenescentpatients, there is a natural decrease in the numbersof cytotoxic T cells leading to active replicationand circulation of EBV-infected B cells (Slotset al. 2006).

Clinical-Pathologic FeaturesOHL in HIV/AIDS is generally seen in the fourthdecade of life, and males are affected more fre-quently (male-to-female ratio 4:1) (Dongo et al.2013; Stojanov and Woo 2015). Men who havesex with men with HIV seropositivity have thehighest prevalence of OHL. OHL presents mostfrequently on the lateral borders of the tongue asan asymptomatic, white, adherent plaque withlinear folds that run parallel to the long axis ofthe lateral tongue (Fig. 11). Other sites include thebuccal mucosa, and lesions are generally bilateral.

OHL is diagnosed by biopsy and confirmationof the presence of EBV by in situ hybridizationstudies. Oftentimes, there is secondary candidosisnoted on the biopsy.

Patient ManagementOHL is a benign lesion and may be the first sign ofHIV infection. As such, all patients carrying thisdiagnosis who are not known to be immunocom-promised should have an HIV test and be evalu-ated for latent immunocompromise. Lesionsresolve with antiretroviral therapy. Treatmentwith systemic valaciclovir and topical treatmentssuch as 25% podophyllin resin, 1% penciclovir, or5% acyclovir have shown some benefits (Wallinget al. 2003; Moura et al. 2010). In patients withiatrogenic immunosuppression, OHLmay resolveon reduction of immunosuppression. Candidosisshould be treated with antifungal agents.


Immune-Mediated and AutoimmuneConditions

BenignMigratory Glossitis (GeographicTongue, Erythema Areata Migrans,Migratory Stomatitis)

Benign migratory glossitis (BMG) is a chronic,benign inflammatory condition of the tonguecharacterized by relapsing-recurring loss of fili-form papillae; it affects 1–2% of the population(Jainkittivong and Langlais 2005). Patients mayseek professional advice because of the unusualappearance of the tongue or increased sensitiv-ity of their mucosa to spicy or acidic food.

Etiology and PathophysiologyThe exact pathophysiology of BMG isunknown. However, it often occurs in atopicpatients, namely, those with or have a historyof asthma, eczema, hay fever, food sensitivities,and other allergies (Goregen et al. 2010). In theabsence of atopy in the patient, a positive his-tory of such conditions may be elicited in first-degree relatives. It is also associated with pso-riasis (especially the generalized pustular form)and Reiter disease. BMG lesions tend to flarewhen patients are under stress or are ill (Milogluet al. 2009).

Clinical-Pathologic FeaturesBMG affects a wide age range; while some reportit to occur mostly in individuals over the age of40, others deem it to be more frequent in childrenwith a decreasing prevalence with increasing age(Banoczy et al. 1975; Assimakopoulos et al.2002). BMG has a female predilection (1.5:1),and patients may be asymptomatic or experienceburning, soreness, and/or sensitivity especiallyupon eating acidic and spicy foods. It most fre-quently presents on the dorsal or ventral tongue.BMG typically begins as one or more depapillatedareas on the dorsal tongue which enlarge to formslightly depressed, red patches with a white sur-rounding rim giving rise to an annular orcircinate appearance. This results in a map-likepattern, hence the name “geographic tongue”(Fig. 12a, b). It is self-limiting and heals within afew days with a variable period of quiescencebefore it recurs. When sites other than the tonguesuch as the lip mucosa, floor of the mouth, or softpalate are affected, it is referred to as migratorystomatitis or stomatitis areata migrans (Fig. 12c).

A biopsy is usually unnecessary if the history istypical but may be performed to confirm thediagnosis.

Patient ManagementIf BMG is asymptomatic, no treatment is indi-cated, and patients should be provided informa-tion and reassurance. Symptomatic BMG lesions

Fig. 11 Hairy leukoplakia:white, adherent plaque withlinear folds running parallelto the long axis of the leftlateral tongue

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may be managed with 2% viscous lidocaineand/or liquid diphenhydramine in equal volumesfor symptom control. Other agents may includetopical steroids and antifungal medications. Moresevere cases may be treated with topical steroidrinses such as dexamethasone oral rinse or steroidgels and creams.

Desquamative Gingivitis

Desquamative gingivitis is a descriptive term thatrefers to gingival erythema that is usually diffuse,sometimes with noticeable peeling of gingival tis-sues. It is a clinical finding that has been associated

with several disorders, some of which may repre-sent true desquamation and loss of epithelium.

Etiology and PathophysiologyDesquamative gingivitis is a clinical findingresulting from three main classes of disordersincluding:

1. Lichen planus or lichenoid mucositis2. Autoimmune vesiculobullous disorders and ,in

particular, mucous membrane pemphigoid andless often pemphigus vulgaris (Scully andPorter 1997; Lo Russo et al. 2008)

3. Contact hypersensitivity reaction (such asplasma cell gingivitis which is often associated

Fig. 12 (a) Benign migratory glossitis characterized bymacular erythema with atrophy of filiform papillae andslightly elevated white, circinate borders. (b) Benignmigratory glossitis characterized by patchy depapillation

of the dorsum with only faint white rim. (c) Migratorystomatitis: white circular and linear lesions of the lowerlip mucosa


with exposure to contactants such as flavoringagents in candies, chewing gum, or dentifrices)

Clinical-Pathologic FeaturesOf the three entities, lichen planus is the mostcommon, and most patients experience mild tomoderate oral sensitivity, pain, and bleeding onbrushing (Lo Russo et al. 2009). Lichen planus,lichenoid lesions, and mucous membranepemphigoid tend to occur in middle-aged females.Because of pain on brushing, there may be abun-dant materia alba on the teeth leading to evenmore inflammation and erythema.

Desquamative gingivitis presents as brightlyerythematous macular and/or diffuse areas of mar-ginal and attached gingiva, usually on the buccalaspect, although the palatal and lingual gingivae

may also be affected (Fig. 13a–c). Ulcers andheaped-up remnants of ruptured bullae may bepresent at the edges of erythema.

In most cases, patients are referred for biopsyor management because good plaque control hasnot resulted in resolution of lesions. A biopsyshould be obtained from peri-lesional tissue; halfshould be sent in formalin for routine histopatho-logic examination, and the other half should besubmitted either fresh if in a medical center or inMichel medium if the tissue is mailed, for directimmunofluorescence studies (Suresh and Neiders2012). The histopathologic features varydepending on the diagnosis. In general, if thepatient already has had a skin biopsy and aknown diagnosis of a blistering disorder, it isusually unnecessary to perform an oral biopsy.

Fig. 13 Desquamative gingivitis: (a) diffuse erythema ofthe buccal attached gingiva without striations in a patientwith lichen planus. (b) Diffuse erythema of the buccalattached gingiva in mucous membrane pemphigoid and

(c) localized erythema of the buccal attached interproximalgingiva of the upper left central and lateral incisor teeth in apatient with pemphigus vulgaris

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Patient ManagementManagement is directed toward treating theunderlying condition. Patients should avoid theoffending contactant if the diagnosis is contacthypersensitivity reaction. Management of lichenplanus and autoimmune disorders is generallywith topical steroids. This may be applied directlyonto the mucosa or within custom trays.Intralesional steroid injections are helpful forlarge ulcers, and systemic therapy may be appro-priate for more severe disease; this is discussed inthe relevant chapters.

Plasma Cell Gingivostomatitis (PlasmaCell Orificial Mucositis)

Plasma cell gingivitis (PCG) also known as aller-gic gingivostomatitis is a rare, yet distinctive,benign inflammatory condition characterized byextensive infiltration of plasma cells within theconnective tissue of the oral mucosa.

Etiology and PathophysiologyThe first cluster of cases was caused by hypersen-sitivity to a component of chewing gum (Kerret al. 1971). Since then, flavoring agents such ascinnamaldehyde in chewing gum and toothpastes,mint candy, and herbs and spices have also beenrecognized as causative factors (Anil 2007).

Clinical-Pathologic FeaturesThis is a condition of adults with no gender pre-dilection. Patients report soreness and sensitivity

especially on eating acidic and spicy foods andsometimes on brushing their teeth. The marginaland attached gingiva presents with diffuse, brighterythema with swelling, edema, and loss of stip-pling similar to the findings in desquamative gin-givitis. Gingival bleeding is common because theepithelium is eroded and inflamed (Fig. 14).Although the gingiva is the most common site ofinvolvement, other oral mucosal sites such as thebuccal and palatal mucosa as well as extraoralsites such as the pharyngeal mucosa may also beaffected.

Conditions such as erythematous/erosive gin-gival lichen planus and mucous membranepemphigoid, or even leukemia, may have thesame clinical presentation. As such, a biopsy isalways required to establish the diagnosis, andthis shows sheets of polyclonal plasma cells.

Patient ManagementSimilar to other hypersensitivity conditions, iden-tifying the causative agent is of prime importance,and patch testing may be useful. Patients shouldkeep a diary of possible exposures, especially toflavoring agents, and whether avoidance resolveslesions. Treatment modalities include topical andsystemic steroids (Solomon et al. 2008). How-ever, lesions will persist as long as the patient isexposed to the antigen. In cases of gross gingivalenlargement (plasma cell granuloma), surgicalexcision is indicated for plaque control, followedby topical steroids.

Fig. 14 Plasma cellgingivostomatitis:manifesting as generalizedmoderate facial gingivalerythema with mild edemain a 32-year-old female


Oral Lichen Planus

Lichen planus (LP) is a common chronic muco-cutaneous condition that may affect the oralmucosa in more than half of the affected individ-uals (Altman and Perry 1961; Cheng et al. 2016).While concomitant presentation of cutaneous andoral LP is common, only 10–15% of patients withoral LP develop cutaneous lesions (Cheng et al.2016). Vulovaginal-gingival and peno-gingivalLP is a subgroup of LP collectively referred to asgingival-genital syndrome that is associated withHLA-DQB1*0201. This condition presents withdesquamative gingivitis and often runs a moresevere course sometimes with buccal mucosafibrosis (Setterfield et al. 2006).

Etiology and PathophysiologyLP is an immune-mediated condition in whichbasal cells are destroyed by cytotoxic CD8+T cells (Lavanya et al. 2011). Although someconsider oral LP to be an autoimmune dis-ease, the target antigen has yet to be identi-fied. Oral LP may be idiopathic, but lichenoidmucosal reactions indistinguishable from idi-opathic LP may be seen in other conditionsincluding:

1. Drug-induced hypersensitivity reactions tomedications such as antihypertensive agents,including β-blockers, angiotensin-convert-ing enzyme inhibitors, and diuretics (inparticular hydrochlorothiazide) and nonste-roidal anti-inflammatory drugs (Yuan andWoo 2015)

2. Hepatitis C especially in patients withHLA-DR6 living around the MediterraneanSea (Carrozzo et al. 2005)

3. Contact hypersensitivity to amalgamrestorations

4. Chronic graft versus host disease5. Thyroid disease (or medications to treat

thyroid disease) (Garcia-Pola et al. 2016)

Because oral LP may be associated with avariety of other conditions, some authorities sug-gest that oral LP is not a single specific disease but

rather a mucosal reaction with a characteristicclinical and histopathologic phenotype.

Clinical-Pathologic FeaturesOral LP is more commonly seen in women (male/female 1:2–3) in the sixth decade (De Rossi andCiarrocca 2014). The WHO diagnostic criteria forlichen planus was modified in 2003 and again in2016 (van der Meij and van derWaal 2003; Chenget al. 2016). Typical oral LP is almost alwaysbilateral and symmetric and affects the buccalmucosa, tongue, and attached gingiva. Lesionsmay be classified into the following, often over-lapping categories:

Reticular/keratotic (classic) oral LP is charac-terized by mostly asymptomatic whiteintersecting loops and lines forming Wickhamstriae or papules on a variably erythematous back-ground (Cheng et al. 2016). Lesions are generallybilateral and involve the buccal mucosa, tonguedorsum and ventrum, lip mucosa, and gingiva;this may be associated with erythema(Fig. 15a–c).

Erythematous/erosive oral LP frequentlyinvolves the gingiva and presents as red, erythem-atous areas of mostly buccal (and less commonlypalatal and lingual) gingiva which is commonlyreferred to as desquamative gingivitis (Fig. 13a).

Ulcerative oral LP presents as ulcerated oralmucosa with a yellow fibrin membrane usuallywith a surrounding erythematous rim and subtleperipheral reticulations (Fig. 16a–d).

Atrophic oral LP is best seen on the tonguedorsum where there is loss of the filiform andfungiform papillae and there is diffuse keratosisor white papules.

Bullous oral LP is extremely rare, and mostbullae break down to form erythematous/erosiveoral LP.

Oral LP that presents with bilateral, symmetricstriations occurring at the typical oral sites maynot require biopsy. Cases that are asymmetric withquestionable striations should be biopsied, anderythematous/erosive lesions presenting asdesquamative gingivitis should also have a por-tion of the biopsy submitted for direct immuno-fluorescence studies to rule out mucousmembrane pemphigoid and other autoimmune

20 M. Jessri et al.

vesiculobullous disorders. “Plaque-type oral LP”occurring as a solitary white plaque or a plaquewithinmore typical oral LP should be viewed withsuspicion, and biopsy is always indicated. Itshould be noted that many oral dysplasias presentwith a histopathologic features of “lichenoidinflammatory infiltrate,” but this should not beautomatically construed as dysplasia arising inoral LP.

Patient ManagementSymptomatic cases are managed with topical ste-roid gels, creams, and rinses. More severe casesmay require systemic steroid therapy in conjunc-tion with hydroxychloroquine, mycophenolatemofetil, or tumor necrosis factor inhibitors. Incases of oral contact lichenoid hypersensitivityreactions, removal of the causative agent such asan amalgam restoration may resolve the lesions(Yuan and Woo 2015). Malignant transformationhas been reported in 0.1–1.0% of oral LP althoughsome of such cases had a history of smoking.

Lupus Erythematosus

Systemic lupus erythematosus (SLE), discoidlupus erythematosus (DLE), and subacute cutane-ous lupus erythematosus (SCLE) are subsets oflupus erythematosus (LE) which is a chronicmultisystemic autoimmune disorder that oftenpresents with oral lesions (Nico et al. 2011;Tsokos 2011; Ranginwala et al. 2012).

Etiology and PathophysiologyLE is an autoimmune disease, and a combinationof genetic, hormonal, and environmental factors(e.g., smoking and exposure to ultraviolet light)may contribute to its development or progression(Tsokos 2011). Genetic predisposition plays apivotal role in pathogenesis of LE, and thisincludes single-gene deficiencies that affect theimmune system (Rullo and Tsao 2013). Anti-bodies produced in this condition target double-stranded DNA, histones, and ribonucleoproteinsand are deposited in several organs including the

Fig. 15 Reticular lichen planus of (a) right buccal mucosa, (b) left buccal mucosa, and (c) dorsum of the tonguepresenting primarily as poorly demarcated keratotic papules


kidney, liver, joints, skin, and mucous membraneresulting in protean clinical presentations(Ippolito et al. 2011).

Clinical-Pathologic FeaturesLE generally affects women of childbearing age(female:male 8–10:1) (Tsokos 2011). The oralmucosa can be affected in the absence of skinlesions in up to 20% of patients with DLE and45% of patients with SLE (Lourenco et al. 2007;Nico et al. 2008). Involvement of oral mucosa isnot a common finding in SCLE, and this has beenattributed to the important role of UV light inpathogenesis of SCLE (Sontheimer 2005).

Extraoral presentations of SLE in the head andneck area include a photodistributed or “butterfly”rash on the malar region, corresponding to thearea of the face that is mostly exposed to the UVlight. Cutaneous lesions of DLE present as atro-phic plaques with follicular plugging and evi-dence of post-inflammatory hyperpigmentation.SCLE is the most photosensitive subtype of LE,

and lesions mostly involve the sun-exposed areaof the skin in the V-area of the neck, upper trunk,dorsum of the hands, and the shoulders(Sontheimer 2005).

Oral lesions of LE cause pain and sensitivityand present as aphthous-like ulcers or poorlydemarcated, red and white, reticulated lesions ofthe buccal, lip, and palatal mucosa (Lourencoet al. 2007) (Fig. 17a, b).

An incisional biopsy and direct immunofluo-rescence studies are required to confirm the diag-nosis. Granular deposition of IgG, IgM, and/orIgA at the basement membrane zone in biopsiestaken from clinically normal skin for SLE, andtaken from lesional tissue in DLE, is diagnostic(lupus band test). Serology is often positive forantinuclear antibody, anti-dsDNA, anti-Smith,anti-ribonucleoproteins, and anti-SSA.

Patient ManagementOral lesions can generally be managed with topi-cal steroids such as clobetasol or fluocinonide if

Fig. 16 Ulcerative lichen planus (all images are from a single patient): reticulated, erythematous, and ulcerated (yellowfibrin membrane) of the bilateral hard palate (a and b) and buccal mucosa (c and d)

22 M. Jessri et al.

lesions are localized, by steroid rinses such asdexamethasone, or by intralesional steroid injec-tions. Systemic therapy is generally initiated andmaintained by the patient’s dermatologist orrheumatologist.

Oral Graft Versus Host Disease

Graft versus host disease (GVHD) is an immune-mediated, multi-organ complication that occursafter allogenic hematopoietic cell transplantation(allo-HCT) used for the treatment of hematologi-cal malignancies and diseases resulting in bonemarrow failure (such as aplastic anemia). Histor-ically GVHDwas classified into acute and chroniccategories based on time from transplantation,with acute GVHD occurring within the first100 days posttransplantation and chronic GVHDas an extension of acute GVHD or developing denovo after 100 days. Current thinking, however,suggests that acute and chronic GVHD have dis-tinct etiologies and clinical manifestations(Pavletic and Fowler 2012).

Etiology and PathophysiologyDisparity in human leukocyte antigens (HLAs)between the donor and recipient is the mostimportant risk factor for developing GVHDbecause of an alloimmune response by the donor’simmune cells against the surface antigens of therecipient’s cells which are mismatched

(Vogelsang et al. 2003). The current guidelinesrecommend 8/8 match between donor and recipi-ent HLA-A, HLA-B, HLA-C, and HLA-DRB loci(Lee et al. 2007b). Other factors such as sex,recipient’s advanced age, source of progenitorcells, and intensity of conditioning regimen mayalso affect the severity of GVHD.

Tissue damage from chemotherapy and radia-tion therapy during pretransplantation condition-ing, infection, and immunosuppressive therapyresults in the activation of antigen-presentingcells. Presentation of mismatched cell surfacehost antigens leads to activation and clonal expan-sion of donor lymphocytes which culminates intissue destruction through pro-inflammatory cyto-kine production, resulting in acute GVHD whichis an exaggerated inflammatory response (Ferraraet al. 2009).

The pathophysiology of chronic GVHD ispoorly understood. One theory proposes chronicGVHD to be an end-stage presentation of allo-reactivity in which donor T cells have differenti-ated into Th2 cells causing activation of B cellsand production of autoantibodies. Alternatively, ithas been postulated that poor/dysfunctionalimmunologic recovery results in altered self-tolerance (Kataoka et al. 2001).

Clinical-Pathologic FeaturesAcute oral GVHD: This tends to occur within daysto weeks of engraftment with erythroderma andsometimes skin blistering. The liver is often

Fig. 17 Oral presentation of lupus erythematous (bothimages are from a single patient). (a) Erythema with slightsurrounding faint white reticulated lesion of the right hard

palatal and (b) white reticulations and erythema of the leftbuccal mucosa


affected leading to jaundice, and involvement of thegastrointestinal tract leads to abdominal pain anddiarrhea (Ion et al. 2014). The oral mucosa isaffected in less than 10% of patients with a medianage of 49 years and a 2:1 male-to-female ratio (Ionet al. 2014). Patients report pain, sensitivity, or aburning sensation. It is characterized bymarked oralmucosal erythema and/or desquamation oftenaccompanied by ulcers and resembles chemother-apy and neutropenic ulcers except that (1) thekeratinized tissues of the hard palatal mucosa andtongue dorsum are often affected and (2) patients areengrafted and no longer neutropenic.

A skin biopsy establishes the diagnosis,although hypersensitivity to medications is animportant differential diagnosis.

Chronic oral GVHD: Lichenoid andsclerodermatous skin involvement, keratocon-junctivitis sicca, liver disease, obstructive lungdisease, gastrointestinal disease, and genital dis-ease with fibrosis are frequently encountered.Unlike acute GVHD, the oral mucosa is affectedin 50–70% of patients with chronic GVHD (Mayset al. 2013). Patients may present with sensitivity,pain, and burning of the mucosa. There is bothxerostomia and hyposalivation caused by destruc-tion of salivary gland parenchyma. The NationalInstitutes of Health (NIH) has devised clinical andhistopathological criteria for scoring chronicGVHD for standardization of diagnosis (Treisteret al. 2010).

The diagnosis is usually made on clinical evalu-ation alone, and a biopsy is not usually necessary.Oral chronic GVHD has three common findings:

(a) Mucosal lesions that are lichen planus-likewith lacey, white reticulations, erythema, andulcerations. The most common sites are thebuccal mucosa, lip mucosa, and tonguemucosa although any mucosa may beinvolved (Fig. 18a–c).

(b) Superficial mucoceles of the palatal and buc-cal mucosa which are occasionally symptom-atic (Fig. 19).

(c) Dry mucosa with little to no floor-of-mouthpooling.

Less frequent findings include:

(a) Scarring and fibrosis leading to trismus andloss of the vestibule, especially in long-standing disease

(b) Rampant caries from hyposalivation(c) Development of oral dysplasia and squamous

cell carcinoma likely due to chronicimmunosuppression

As with other similar lesions in the mouth,these take the form of leukoplakia and its variants,erythroplakia, ulcers, and mass lesions. The riskof developing secondary cancer is greater inpatients surviving 10 or more years after allo-HCT transplant (Demarosi et al. 2005).

Patient Management and FutureDirectionsAcute GVHD is managed with calcineurin inhib-itors (cyclosporine or tacrolimus), high-dose ste-roids, sirolimus, and mycophenolate mofetil.

Chronic GVHD of the oral mucosa is usu-ally successfully managed with a combinationof topical steroids, topical tacrolimus,intralesional steroid injections, and/or sys-temic steroids and immunosuppressive ther-apy, depending on the severity of oraldisease and the extent of involvement of theskin and other organ systems. Ulcers shouldbe cultured to rule out herpes simplex virusinfection. Hyposalivation is managed with fre-quent sips of water, and cholinergic agents,such as pilocarpine and cevimeline, and topi-cal fluoride applications are helpful for theprevention of caries. Scarring and trismuscan be managed with stretching exerciseswith/without stretching devices, intralesionalsteroid injections, and surgery to releasefibrotic bands. Regular follow-up is essentialfor early detection of dysplasia and squamouscell carcinoma.

There is ongoing research into managingGVHD by using targeted therapies to reduce cyto-kine production, modulate the activity of antigen-presenting cells, and control T-cell numbers andactivity.

24 M. Jessri et al.

Erythema Multiforme

Erythema multiforme (EM) is an acute hypersensi-tivity reaction with mucocutaneous manifestations.It is considered distinct from Stevens-Johnson syn-drome and toxic epidermal necrolysis which arenecrolytic syndromes with the latter being themore severe form (Bastuji-Garin et al. 1993).

Etiology and PathophysiologyEM is a hypersensitivity reaction primarily to aninfectious agent with more than 70% of casesassociated with herpes simplex virus (HSV) infec-tion, as well as with M. pneumonia infection usu-ally in children (Sun et al. 2003; Schalock et al.2006). Hypersensitivity to medications such asantibiotics (e.g., penicillins and sulfonamides),anticonvulsants (phenytoin), or analgesics(NSAIDs) forms a minority of cases (Sanchis

Fig. 19 Superficial mucocele (arrow) on the hard palatalmucosa of a patient with oral chronic graft versus hostdisease

Fig. 18 Oral chronic graft versus host disease (all imagesare from a single patient). (a) Diffuse erythema involvingmore than 75% of the right buccal mucosa. (b) Diffuseerythema and linear ulceration of the left buccal mucosa.

(c) Erythematous and diffuse keratotic changes of the hardpalate with multiple superficial mucoceles (Courtesy ofDr. Nathaniel Treister, Harvard School of Dental Medicine,Boston, MA, USA)


et al. 2010; Langley et al. 2016). Asymptomatic(subclinical) reactivation of HSV may also causethis condition. In addition, some have considereda role for genetic predisposition to EM with HLADQ3, HLA-B35, HLA-A33, HLA-DR53, andHLA-DQB1*030 being associated with recurrentEM (Schofield et al. 1994).

Clinical-Pathologic FeaturesAdults between the age of 20 and 40 are mostcommonly affected, with 20% of the cases occur-ring in children with a slight predilection forfemales. As discussed above, a large proportionof patients have a recent history of HSV infection.EM is categorized into minor and major types andchronic recurrent oral erythema multiforme. Inminor EM, there is little-to-no mucous membraneand minimal (10%) skin involvement; the majortype however is characterized with more exten-sive mucous membrane and skin involvement.Chronic recurrent oral EM is nearly always asso-ciated with HSV infection, and patients may expe-rience several episodes a year (Farthing et al.2005).

Erythematous pruritic papules appear on theskin of the extremities, some of which developtypical “target,” “bull’s eye,” or “iris” lesions.Such lesions are generally less than 3 cm in diam-eter and are composed of a central necrotic anderythematous disc surrounded by a pale edematousring and an outer circle of dusky erythema(Auquier-Dunant et al. 2002). Cutaneous lesionsprogress centripetally to involve the trunk. The oralmucosa is affected in 20–70%of patients, and thesepresent as painful ovoid or irregular ulcers on anymucosal surface with a background of moderate tosevere erythema. Hemorrhagic crusts of the lipvermilion are a common but are not an invariablefinding (Fig. 20a–d) (Farthing et al. 2005).

While cultures for HSVare usually negative inEM patients, elevated serum IgM and IgG (at leastfour times over baseline) to HSV is supportive ofthe diagnosis. Lesional tissue may also be positiveby polymerase chain reaction for HSV. For thediagnosis of M. pneumonia, detection of IgM forplasma membrane antigens protein 1 and protein116 by enzyme immunoassay is the most sensitive(Lee et al. 2017).

Patient ManagementA careful history taking and bloodwork as men-tioned above are essential for establishing whetherthe trigger is infectious or medication-induced.EM is self-limiting and, management is directedtoward pain control with topical anesthetics andanalgesics, supportive care such as hydration, andpromotion of healing of mucocutaneous lesionswith topical and/or systemic steroids. Daily anti-viral therapy has been shown to prevent recurrentEM in patients with viral trigger, and this in itselfmay be a useful diagnostic tool (Tatnall et al.1995).

Precancerous and Cancerous Lesions

Leukoplakia and ProliferativeVerrucous Leukoplakia

Leukoplakia is a clinical diagnosis defined byWHO as a white plaque of questionable risk havingexcluded (other) known diseases or disorders thatcarry no increased risk for oral cancer(Warnakulasuriya et al. 2007). It is the most com-mon premalignant (potentially malignant) condi-tion of the oral cavity. Because all other knowndisorders that carry no increased risk for oral cancermust be ruled out, the diagnosis of leukoplakia is,by definition, one of exclusion.While some lesionsmay be ruled out on clinical features alone, otherswill require a biopsy for definitive diagnosis.Manyconditions already discussed earlier in this chapterare white but not leukoplakias.

Approximately 40% of true leukoplakias showhistologic evidence of dysplasia, carcinoma insitu, or invasive squamous cell carcinoma(SCC). The other 60% will show hyperkeratosisor parakeratosis, acanthosis, or atrophy, with orwithout inflammation; these have been given thename keratosis of unknown significance (KUS).

Etiology and PathophysiologyRisk factors for the development of intraoral leu-koplakia are similar to those for oral SCC and assuch include cigarette smoking, excessive alcoholconsumption, areca nut use, personal or familialhistory of cancer or cancer therapy, chronic

26 M. Jessri et al.

immunosuppression, age, and some syndromes(such as dyskeratosis congenita). Other risk fac-tors include ultraviolet light damage for lesions ofthe vermilion and human papillomavirus in asmall number of cases (Bagan et al. 2010; Wooet al. 2013).

Regardless of histologic grade, oral leukopla-kia has a heterogeneous molecular profile andexhibits loss of heterozygosity at 3p and/or 9pwhich is associated with an increased risk ofmalignant transformation (Rosin et al. 2000;Lingen et al. 2011; Gomes et al. 2015). Aneu-ploidy and hypermethylation have been reportedin oral dysplastic lesions, and aneuploidy hasbeen positively associated with higher histopath-ologic grade of dysplasia (Lingen et al. 2011).Mutation and loss of heterozygosity of TP53 andloss or overexpression of p53 is a frequentmolecular finding in dysplastic leukoplakias

(Rosin et al. 2000; Lingen et al. 2011). Althoughinactivating mutations in TP53 are generallyconsidered “driver mutations” in carcinogenesis,overexpression of p53 is due to stabilizing muta-tions in the gene that prolongs the half-life of theprotein (Lingen et al. 2011). Overexpression ofmatrix metalloproteinase 1 and 9 mRNA has alsobeen associated with the progressive phenotypeof dysplastic lesions (Jordan et al. 2004).

Clinical-Pathologic FeaturesLeukoplakia most often presents as a solitarylocalized white plaque and less commonly asmultifocal or extensive lesions that affect contig-uous sites.

Oral localized leukoplakia (OLL): OLL con-stitutes 85% of all oral potentially malignant dis-orders with a global prevalence of 2–4%. Itusually affects individuals in the sixth decade of

Fig. 20 Recurrent erythema multiforme secondary toreaction to fluconazole (all images are from a singlepatient): (a) crusting of the upper lip with ulceration ofthe wet-dry border of the upper lip, extending to upper

labial mucosa. (b) Ulceration of the right hard palate withdiffuse erythema. (c) Erythema and ulceration of thetongue dorsum. (d) Ulceration of the right ventral tongue


life or older, with increasing prevalence withincreasing age. The male/female is approximately2–3:1, and 38–62% of lesions occur in smokers(Woo et al. 2014; Maia et al. 2016; Naveen-Kumar et al. 2016). It is generally asymptomatic,and the tongue, gingiva, buccal mucosa, and pal-atal mucosa are the most commonly affected sites(Liu et al. 2012).

Leukoplakia is classified as follows:

1. Homogenous leukoplakia. This presents as awell-demarcated, uniform white plaque that isoften fissured (Fig. 21a).

2. Nonhomogenous leukoplakia. This takes sev-eral forms.a. Verrucous leukoplakia which has, at least

focally, a rough surface and may be leatheryin appearance; this also tends to have a well-demarcated border and often occurs on thegingiva (Fig. 21b).

b. Nodular leukoplakia which has, at leastfocally, a nodular surface and is also welldemarcated, although this may be difficultto distinguish from, or coexist with,verrucous leukoplakia, and it may be usefulto combine verrucous and nodular leuko-plakia into a single category.

c. Erythroleukoplakia. This has areas of ery-thema within the leukoplakia that may bepatchy or speckled (speckled leukoplakia);the erythematous component is generallynot well demarcated (Fig. 21c).

The rate of progression to oral cancer has beenreported to be 1–7% for homogenous leukoplakia,4–15% for verrucous leukoplakia, and 18–47%for erythroleukoplakia (Hsue et al. 2007; Liuet al. 2012; Anderson and Ishak 2015). However,morsicatio mucosae oris and benign alveolar ridgekeratosis which have no malignant potential maybe historically included in the category of leuko-plakia resulting in dilution and underrepresenta-tion of the true prevalence of dysplasia andprogression to cancer (Woo et al. 2014; van derWaal 2015).

In general, true leukoplakias do not regress butshow progression and enlargement over time

either noticeably or at a barely perceptible rate.The appearance of the lesion may also changefrom being homogenous to nonhomogenous andfrom being soft to being firm and indurated.

Proliferative verrucous leukoplakia (PVL):Although the WHO considers PVL to be a subsetof conventional localized leukoplakia, there aremany differences between the two which maywarrant classifying it separately (Table 1). PVLis characterized by relentlessly progressiveinvolvement of the oral mucosa by white plaques,often verrucous and fissured, at multiple, non-contiguous sites, or it may present as a singlelarge lesion with or without involvement of con-tiguous sites; a size of 3 cm2 is often used as acriterion for this diagnosis in a single large lesion(Fig. 22a–d). Although the average age at diagno-sis of PVL is in the seventh decade, most patientswill report that lesions have been present for yearsprior (Bagan et al. 2010, 2011). A homogenousform of PVL may exist but would be rare. As itsname suggests, the most common form is theverrucous/nodular form. However, proliferativeerythroleukoplakia is a variant that is often mis-taken for oral lichen planus because of its wide-spread, often bilateral nature, with red and whiteareas, and sometimes trabecular keratosis thatmay be mistaken for reticulations. As such, theless specific term “proliferative leukoplakia” maybe a more appropriate name for this condition.

All patients with leukoplakia must be biopsiedto establish a definitive diagnosis. Lesions thatmay have been clinically diagnosed as leukopla-kia may in fact be histopathologically frictionalkeratosis, candidosis, or some other white lesion.In one study, this constituted approximately 75%of all “clinical leukoplakias” (Woo et al. 2014).Between 39% and 53% of localized leukoplakiasshow evidence of epithelial dysplasia or neoplasiaat the time of diagnosis, and almost one third ofdysplastic lesions progress to form invasive can-cer (Brouns et al. 2014; Woo et al. 2014).

In lesions that are large, multiple biopsiesshould be performed such as from a white area,from a red area, and from an indurated area (Para-shar 2014; Gomes et al. 2015). In one study ofincisional biopsies and subsequent excision oforal leukoplakias, 29% of the patients with

28 M. Jessri et al.

single-site biopsy and 12% of the patients withmultiple-site biopsies were deemedunderdiagnosed. In addition, 12% of patientswith single-site biopsy and only 2% of patientswith multiple-site biopsies had unexpected carci-noma which were diagnosed in later resection ofthe lesions (Lee et al. 2007a).

A recent systematic review of the literatureshowed patients with PVL to have undergone atleast nine biopsies during their follow-up period(mean: 7 years; range: 0.5–15 years) (Abadie et al.2015). Sequential biopsies are essential for monitor-ing lesions of PVL because most lesions begin asKUS and progress to dysplasia and invasive cancerover decades (Parashar 2014; Abadie et al. 2015).

Patient Management and FutureDirectionsLocalized leukoplakia exhibiting keratosis ofunknown significance: KUS lesions should bereevaluated by the clinician to determine whetherthey may represent reactive/frictional keratoses.Criteria for reactive lesions include poor demar-cation, lack of fissuring, location at a site that caneasily be traumatized, waxing and waning naturewith even complete resolution, and then recur-rence. Discussion with the pathologist is veryhelpful. If the clinical lesion is one of a trueleukoplakia, narrow excision or ablation shouldbe considered if the lesion is small, so that surgeryis minimally morbid, and if the patient is young.

Fig. 21 (a) Homogenous localized leukoplakia: sharplydemarcated white plaque of the right buccal mucosa thatshowed moderate dysplasia (Courtesy of Dr. NathanielTreister, Harvard School of Dental Medicine, Boston,

MA, USA). (b) Erythroleukoplakia of the right dorsaland ventrolateral tongue that on excision revealed a squa-mous cell carcinoma. (c) Verrucous leukoplakia of theright ventrolateral tongue


Table 1 Comparison between localized leukoplakia and proliferative leukoplakia

Feature Leukoplakia Proliferative leukoplakia

Demographics Older males Older females

Associationwith smoking

High association with smoking (38–62%)(Maia et al. 2016; Naveen-Kumar et al.2016)

Low association with smoking (up to 42%) (Cerero-Lapiedra et al. 2010)

Distribution Single site Multifocal or extensive contiguous sites

Common sites Tongue, gingiva, and buccal mucosa Gingiva, alveolar mucosa, and palatal mucosa

Histopathologyat first biopsy

~ 40% dysplastic or SCC <10% dysplastic or SCCMostly verrucous hyperplasia or KUS

Risk ofmalignanttransformation

Overall: 1–15%Annual: 1–3%

Overall: 60–100%Annual: 10%

Architecture Could be homogenous ornonhomogenous

Mostly nonhomogenous, usually verrucous/nodular orerythroleukoplakic

Management Excision or ablation Difficult to manage because of the extent of the lesion;follow-up and excision of invasive cancers as theydevelop

SCC squamous cell carcinoma, KUS keratosis of unknown significance

Fig. 22 Proliferative verrucous leukoplakia. (a) Partiallydemarcated, white plaque on maxillary buccal gingiva. (b)Well-demarcated verrucous white plaque on the palatalmucosa. (c) Involvement of ~50% of the right buccal

mucosa with a poorly demarcated, fissured, fairly homog-enous white plaque. (d) Partially demarcated plaque of themandibular buccal gingiva and vestibule

30 M. Jessri et al.

Research on the molecular changes in KUSwould help clarify whether they exhibit similargenomic alterations as dysplasia or even SCC.

Localized leukoplakia with dysplasia: Somebelieve that mild dysplasias may regress, and assuch, watchful waiting is appropriate (Lodi andPorter 2008). It is more likely that mild reactiveepithelial atypia that may be seen in frictionalkeratoses and in other benign inflammatory con-ditions has been diagnosed as mild dysplasiaand, as such, regressed with treatment or sponta-neously. Some believe that even moderate-to-severe dysplasias do not require treatment. How-ever, molecular studies have shown that thesecarry similar mutations as SCC (Lingen et al.2011). As such, they are not likely to regressand more likely to progress, although the timeto development of SCC varies greatly frompatient to patient (Dost et al. 2014). OLL withmoderate-to-severe dysplasia should be excisedwith clear margins if clinically appropriate (suchas young patients with small lesions), and allpatients should be followed up indefinitely forrecurrence or the development of newleukoplakias at a noncontiguous site. Recurrencehas been reported in approximately 7–38% oflesions based on the definition of leukoplakia,site, and treatment (such as laser ablationvs. resection) (Lodi and Porter 2008;Kuribayashi et al. 2012). Patients with leukopla-kia exhibiting carcinoma in situ and invasiveSCC should be referred to a cancer center formanagement.

Proliferative verrucous leukoplakia: Periodicmultisite biopsy especially of verrucous, ery-thematous, indurated, and bulky areas isrecommended. Areas that show moderate-to-severe dysplasia should be monitored closely orexcised if possible, although in most cases, it isnot possible to obtain margins free of dysplasia,and dysplastic cells repopulate the surgical site.Areas that show carcinoma in situ or invasivecarcinoma require complete excision with theunderstanding that the margins should be freeof carcinoma, but will likely not be free of dys-plasia or KUS.

Within 4–12 years of follow-up, 74% of PVLprogress to cancer (Cabay et al. 2007). Because

many initial biopsies show KUS, this is evidencethat KUS lesions are precancerous althoughwithout the histopathologic phenotype ofdysplasia.

Adjunctive aids such as the use of toluidineblue or autofluorescence techniques may be usefulin such targeted cases and especially for follow-ups. However, findings must be interpreted withcaution because of low specificity of such tools(Bhatia et al. 2013; Bhatia et al. 2014). Moredetail about these devices is found in the chapteron Oral Mucosal Malignancies.

Research on the molecular changes in PVL,especially the earlier lesions that show onlyKUS, would help clarify whether they exhibitsimilar genomic alterations as dysplasia or evenSCC. If so, targeted therapy may be useful for themanagement of this condition.

Erythroplakia

Erythroplakia is a premalignant lesion character-ized by a red plaque and is strongly associatedwith dysplasia and squamous cell carcinoma(Warnakulasuriya et al. 2007). According toWHO definition, erythroplakia is “a fiery redpatch that cannot be characterized clinically orpathologically as any other definable disease”(Axell et al. 1984; Warnakulasuriya et al. 2007).Therefore, similar to leukoplakia, the diagnosis oferythroplakia is based on exclusion of other redlesions of the oral cavity (Shafer and Waldron1975).

Etiology and PathophysiologyThis is a premalignant condition. Similar to oralsquamous cell carcinoma, smoking, excessivealcohol consumption, personal or familial historyof cancer, male gender, advanced age, history ofcancer therapy, and prolonged immunosuppres-sion are the major risk factors for developingerythroplakia (Shafer and Waldron 1975).Erythroplakia is uncommon, and as such there islimited data on its molecular characteristicsalthough mutations in TP53 have been reported(Reichart and Philipsen 2005; van der Waal2009).


Clinical-Pathologic FeaturesOral erythroplakia is most commonly seen in themiddle aged and the elderly with a substantiallyhigher predilection for males (Reichart andPhilipsen 2005). Lesions are usually asymptom-atic, and the most commonly involved sitesinclude the floor of the mouth, tongue, soft palate,and buccal mucosa. Erythroplakic lesions appearas smooth or granular, velvety plaques with gen-erally well-demarcated margins (Fig. 23).

All require biopsy, and over 70–90% of lesionsexhibit carcinoma in situ and invasive squamouscell carcinoma (Shafer and Waldron 1975;Mashberg and Feldman 1988).

Patient ManagementLesions that exhibit dysplasia or squamous cellcarcinoma require excision or resection. Malig-nant transformation occurs in 14–50% of cases(Reichart and Philipsen 2005). As such, closefollow-up of the patient for life is recommended.

Oral Submucous Fibrosis

Oral submucous fibrosis (OSF) is an insidious,potentially malignant lesion caused by chewingareca nut, with 7–13% of cases exhibiting trans-formation to squamous cell carcinoma (Pindborget al. 1984; Murti et al. 1985). It is characterizedby progressive mucosal fibrosis that can affectmost of the oral cavity including the lips andbuccal mucosa resulting in trismus. In advanced

cases, fibrosis of the upper third of esophagealmucosa may result in dysphagia.

Areca, which is the endosperm of Areca cate-chu palm tree, is commercially available in SouthAsia as the main component of betel quid andgutkha which are used for their stimulant or psy-choactive properties (Arakeri and Brennan 2013).Betel quid (“paan”) is composed of the Piper betelleaf wrapped around the chopped areca nut,chopped tobacco leaves, and other componentssuch as slaked lime and spices. Gutkha is increas-ingly replacing betel quid in popularity. It is usu-ally sold in prepackaged sachets and is composedof areca nut, powdered tobacco, slaked lime, cat-echu (acacia extract), and flavorings.

Etiology and PathophysiologyAreca nut contains alkaloids (the most potent ofwhich is arecoline), flavonoids, and copper, all ofwhich interfere with collagen metabolism(Tilakaratne et al. 2006). Chronic exposure toalkaloids induces synthesis of interleukin6, tumor necrosis factor, and transforming growthfactor beta (TGF-β) which modulate differentia-tion of fibroblasts resulting in accumulation ofcollagen (Rajalalitha and Vali 2005). Flavonoidssuch as tannins and catechins stabilize collagenmolecules and inhibit collagenase throughincreasing the local concentration of cytokinesand TGF-β (Arakeri and Brennan 2013). Thehigh content of copper in areca nut upregulateslysyl oxidase which is essential to collagen cross-linkage (Arakeri and Brennan 2013).

Fig. 23 Erythroplakia ofthe right maxillaryedentulous alveolar ridge

32 M. Jessri et al.

The carcinogenic properties of betel quid andgutkha are due to isolated or synergistic action oftobacco and areca nut (Nair et al. 2004; Arakeriand Brennan 2013). Carcinogenic effects of arecanut are attributed to polyphenols, alkaloids (mostimportantly, arecoline), metabolites of alkaloids(e.g., arecoline N-oxide), and areca nut-specificnitrosamines such as N-nitrosoguvacoline,N-nitrosoguvacine, 3-propionaldehyde, and3-propionitrile (Angadi and Rao 2011; Kuo et al.2015). In chronic exposure to such molecules,there is reduced cellular antioxidant glutathioneresulting in increased oxidative stress and subse-quent DNA damage which, when unrepaired, maylead to gene rearrangements and deletions impli-cated in carcinogenic process (Nair et al. 2004). Ifleft unrepaired, DNA damage is a threat to geno-mic integrity, and their misrepair can potentiallylead to activation of the apoptosis pathway, induc-ing chromosomal rearrangements, DNA dele-tions, and other deleterious mutations implicatedin carcinogenic process.

Clinical-Pathologic FeaturesAlthough there is a dose-dependent relationshipbetween chewing areca nut and the developmentof OSF, currently OSF is not only more commonin younger individuals (in the second or thirddecade), but in addition younger patients (under40 years of age) have been reported to developOSF in response to shorter periods of exposure toareca nut compared to older individuals (Jacobet al. 2004; Ranganathan et al. 2004). OSF ismore common in males. Often times, patientsreport pain, burning, and sensitivity in themouth. The buccal mucosa, tongue, and soft pal-ate are among the most commonly affected sitesalthough in late stages, the disease might affect theentire oral mucosa and include the oropharynx.

Clinical presentation of OSF depends on stag-ing which is based on the degree of fibrosis andmouth opening (More et al. 2012). Early clinicallesions (stage 1) are characterized by stomatitis,including vesicle formation, petechiae, post-inflammatory hypermelanosis, and ulceration. Inmoderately advanced lesions (stage 2), themucosa has a marble-like pallor and fibrousbands that can be palpated in the buccal mucosa,

and there is trismus (Fig. 24a–c). Such fibrosismay be extensive in stage 3 disease (More et al.2012).

A biopsy should be performed when leukopla-kia, erythroplakia, persistent ulceration, or a masslesion is noted, suspicious for transformation todysplasia and/or carcinoma.

Patient ManagementCurrently, there is no cure of OSF, and it does notregress with cessation of the habit. Early stages ofOSF can be treated with intralesional steroidinjections (Arakeri and Brennan 2013). Patientwith trismus may benefit from stretching the jawusing stacked tongue depressors or employing jawrehabilitation devices to increase and maintainrange of motion. Advanced cases may requiresurgical release of the fibrotic bands (Arakeriand Brennan 2013; Warnakulasuriya and Kerr2016). OSF is a potentially malignant disorderthat often displays evidence of dysplasia in theoverlying epithelium with 7–13% of the patientsdeveloping oral squamous cell carcinoma. Assuch, close, long-term follow-up is recommended(Yoithapprabhunath et al. 2013).

Actinic Cheilitis (Actinic Cheilosis, SolarCheilosis, and Farmer’s Lip)

Actinic cheilitis (AC) is a disorder that commonlyaffects the vermilion border of the lower lip as aresult of sun damage. It is considered a potentiallymalignant condition.

Etiology and PathophysiologySimilar to actinic keratosis, which is a solitarykeratotic and dysplastic lesion, AC develops dueto chronic exposure of the lip vermilion to ultra-violet (UV) light, in particular UVB. UVB cancause mutations in tumor suppressor gene TP53and other mutational events increasing the risk fordeveloping squamous cell carcinoma.

Clinical-Pathologic FeaturesAC is normally seen in the middle-aged popula-tion with a strong predilection for Caucasian men(male/female of 10:1), and patients may report


pain and/or sensitivity. Most patients relate a his-tory of long-term sun exposure whether fromwork (such as farming or outdoor occupations)or from recreational activities (such as boating orgolfing). Fair-skinned individuals (skin photo-types I and II) or those with a history of sunburnsduring childhood are at high risk for developingAC. The most frequent clinical findings includeblurring of the vermilion-skin interface, dryness,fissuring, atrophy, scaly changes of the lower lip,and less commonly swelling and erythema(Fig. 25). Early lesions appear as pale, blotchy,smooth areas and/or dry fissures on the lower lipthat slowly progress to form rough, scaly areasor firm keratotic papules and ulcers which mayrepresent actinic keratosis or even squamouscell carcinoma. Lesions may also appear as

leukoplakia or erythroleukoplakia (Camara et al.2016).

A biopsy to rule out dysplasia is indicated incases with localized, scaly, or firm papules becausethis may represent actinic keratosis, which is bydefinition at least dysplastic if not outright squa-mous cell carcinoma (Camara et al. 2016).

Patient ManagementAC is an irreversible condition and has the poten-tial for slow progression to squamous cell carci-noma. Patients should have regular follow-ups,limit sun exposure, and apply sunscreen routinely(Goldman 2015). Lesions exhibiting dysplasiamay be treated with either topical therapies such5-fluorouracil, imiquimod and cryotherapy,vermilionectomy, or laser ablation (Shah et al.

Fig. 24 Submucous fibrosis: (a) reduced mouth openingat 31 mm. (b) Diffuse whiteness with marbled-like pallorand macular erythema of right buccal mucosa with

palpable fibrotic bands. (c) Diffuse whiteness of rightventrolateral tongue

34 M. Jessri et al.

2010). Squamous cell carcinoma is treated withsurgical excision.

Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is theeighth most common cancer worldwide (Scullyand Bagan 2009). OSCC may be preceded by orarise in a setting of leukoplakia, erythroplakia, orOSF. Considering the complexity and importanceof a timely diagnosis and correct management inthe prognosis of patients, OSCC has beendiscussed in greater detail in a separate chapteron Oral Mucosal Malignancies.

Etiology and PathophysiologyRisk factors for developing OSCC are similar tothat of oral epithelial dysplasia and include historyof tobacco use, excessive alcohol consumption,areca nut use, history of cancer and cancer treat-ment, chronic immunosuppression and autoim-mune disease, genetic and dietary factors,advanced age, male gender (likely related tohabits), and human papillomavirus (HPV) infec-tion (Warnakulasuriya et al. 2005; Scully andBagan 2009). While tobacco use is perceived tobe the major contributing factor in etiology ofOSCC in low- and middle-income countries,HPV infection has been associated with pharyn-geal and base-of-tongue cancer in youngerpopulations with lower or no tobacco exposure(Sturgis and Cinciripini 2007).

Environmental carcinogens such asbenzopyrenes and nitrosamines from cigarettesmoke and arecoline from areca nut cause OSCCand induce somatic mutations. Mutations in TP53,CDKN2A, PIK3CA, NOTCH, EGFR, and Wntpathways have been reported in head and necksquamous cell carcinoma (Agrawal et al. 2011;Stransky et al. 2011; CancerGenomeA-tlasNetwork 2015). Patients with familiar cancersyndromes such as dyskeratosis congenita,Fanconi anemia, and Bloom syndrome are athigher risk for developing oral squamous cellcarcinoma because of inherited mutations (Savage1993; van Monsjou et al. 2013; Sarode et al.2016).

Clinical-Pathologic FeaturesTraditionally, OSCC affects older males (male-to-female ratio 2:1) and often presents as leukopla-kia, erythroplakia, PVL, nonhealing ulcers, ormass lesions (Fig. 26a, b). Lesions tend to beindurated and most often affect ventrolateraltongue and floor of the mouth. Early lesions aregenerally painless or have minimal symptoms,while advanced lesions may present with pain,paresthesia, or tooth mobility.

Patient ManagementTreatment of OSCC is highly dependent uponclinical staging. Once a tissue diagnosis isestablished, intraoral and extraoral imagingsuch as panoramic radiographs, computedtomography (CT), positron emission

Fig. 25 Actinic cheilitischaracterized by blurring ofthe vermilion-skin borderand moderate erythema andvascular ectasia withscattered faint whitechanges; this is particularlynoticeable on the lower lip


tomography (PET) scan, and magnetic resonanceimaging (MRI) are used to determine clinicalstaging of the tumor. Stage I and II tumors gen-erally have favorable prognosis and are typicallytreated with en bloc resection with or withoutlymph node dissection (Haddad et al. 2008).Many patients are diagnosed in late stages(stages III and IV) and are treated via a multi-disciplinary approach including surgery andadjuvant or primary radiation and chemotherapy(Haddad et al. 2008). EGFR is overexpressed inmost OSCC tumors, and consequently,cetuximab, a monoclonal antibody againstEGFR, shows promise in the treatment ofOSCC (Laimer et al. 2007; Dai et al. 2014;Martinez-Useros and Garcia-Foncillas 2015).Early diagnosis strongly impacts survival, andthe 5-year survival rate is over 80% for stage Itumors and <30% for stage IV tumors. Patientsshould be followed up indefinitely because theyare at high risk for developing a secondmalignancy.

Conclusion and Future Directions

Red and white lesions of the oral cavity include awide variety of conditions; these range from reac-tive reversible conditions such as frictional

keratoses to potentially malignant and malignantlesions such as oral leukoplakia. Lesions can besmall and isolated or involve the entire mucosa.Similarly, lesions may be entirely asymptomatic ormay result in mucosal sensitivity, burning, and insome cases severe pain. Management of orallesions is based on their etiology and prognosis.Advances in basic science and, in particular, next-generation sequencing are improving our under-standing of the etiology, development, and progres-sion of malignant and potentially malignant lesions(Jessri and Farah 2014). As this is translated intoclinical practice, it will lead to earlier and moreaccurate diagnosis, resulting in better managementand targeted therapy in appropriate cases.

Cross-References

▶Clinical Evaluation of Oral Diseases▶Cutaneous Pathology of the Head and NeckRegion

▶Gingival Pathology▶Head and Neck Malignancies▶ Interface Between Oral and Systemic Health▶LaboratoryMedicine and Diagnostic Pathology▶Normal Variation in the Anatomy, Biology andHistology of the Maxillofacial Region

▶Oral and Maxillofacial Fungal Infections

Fig. 26 Oral squamous cell carcinoma. (a) Erythroplakiaof the floor of the mouth in a male patient with 40-yearhistory of cigarette smoking (60 pack-years). Patient pre-viously treated with T3N0 HPV-negative oropharyngealsquamous cell carcinoma, with recent diagnosis of lungcarcinoma. Incisional biopsy of the erythroplakia revealed

moderately differentiated invasive squamous cell carci-noma. (b) Erythroleukoplakia of the left tongue withthick exophytic plaques in a female patient withnon-Hodgkin lymphoma status post-allogenic stem celltransplant (10 years prior). An incisional biopsy of thelesion revealed invasive squamous cell carcinoma

36 M. Jessri et al.

http://link.springer.com/Clinical Evaluation of Oral Diseases

http://link.springer.com/Cutaneous Pathology of the Head and Neck Region

http://link.springer.com/Cutaneous Pathology of the Head and Neck Region

http://link.springer.com/Gingival Pathology

http://link.springer.com/Head and Neck Malignancies

http://link.springer.com/Interface Between Oral and Systemic Health

http://link.springer.com/Laboratory Medicine and Diagnostic Pathology

http://link.springer.com/Normal Variation in the Anatomy, Biology and Histology of the Maxillofacial Region

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▶Oral Lichen Planus▶Oral Manifestations of Systemic Diseases▶Oral Mucosal Malignancies▶Oral Ulcerative Lesions▶Oral Vesicular and Bullous Lesions▶Orofacial Pain Associated with Oral MucosalDisease and Cancer

▶ Pharmaco-Therapeutic Approaches in OralMedicine

▶ Soft and Hard Tissue Operative Investigationsin the Diagnosis of Oral Disease

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