QUINTESSENCE INTERNATIONAL ORAL MEDICINE

Irène Hitz Lindenmüller of the : Inflammatory diseases

Irène Hitz Lindenmüller, DDS, Dr med dent1/Peter H. Itin, MD, Prof Dr med2/Susanna K. Fistarol, MD3

The sensitive transitional skin of the lips is a favored site for systemic disorders such as or in allergic primary skin diseases, especially eczematous dermatitis. An diseases. This article presents the most frequent and the most inflammatory condition of the lips, eg chapped lips ( important forms of inflammatory cheilitis. (Quintessence Int sicca) in atopic eczema, may be the only manifestation of a skin 2014;10:875–883; Originally published in Quintessenz 2013; disease or appear as part of a generalized dermatosis. 64(2):195–204; doi: 10.3290/j.qi.a32638) Inflammatory changes to the lips also occur in the context of

Key words: , atopy, cheilitis glandularis, cheilitis simplex, contact eczema, granulomatous cheilitis, , -licking eczema, lupus erythematosus

The lip vermilion forms the transitional zone between CHEILITIS SIMPLEX skin and mucosa.1 With only three to five layers of epi- dermal cells, it is much thinner than the rest of the facial The terms “common cheilitis”, “cheilitis sicca”, “dehy- skin.2 The lip has no hair follicles. It contains neither dration cheilitis”, “exfoliative cheilitis”, and “chapped sebaceous nor sweat glands.1 This is why it lacks the lips” are used as synonyms of cheilitis simplex.3 Some of protective hydro-lipid layer usually found on the rest of these terms reveal the etiology and clinical symptoms the skin, an emulsion of water and fat that keeps the of the condition. The two most common causes of chei- skin soft and supple and also presents an effective bar- litis simplex are dehydration and/or mechanical irrita- rier against invasion by pathogens.2 The lip vermilion is tion. Wind and cold encourage dehydration of the lips. hence more susceptible to dehydration and irritation The desire to moisten dry lips constantly with saliva and less resistant to than the rest of the body’s further promotes the development of cheilitis simplex.3 skin. Therefore, inflammation of the lips, known as chei- People with atopic eczema are particularly predisposed litis, is a widespread complaint. The most common to cheilitis. Cheilitis sicca is also a typical dose-depen- causes of cheilitis are contact allergy, irritation, or atopy. dent, almost inevitable side effect of systemic retinoid treatment (Fig 1). Mechanical damage to the lips due to repeated chewing on the upper or lower lip (cheilopha-

1 Senior Physician, Department of Oral Surgery, Oral Radiology and Oral Medicine, gia) will also lead to the picture of cheilitis simplex. School of Dental Medicine, University of Basel, Basel, Switzerland. Cheilophagia (in French also known as “tic de lèvres”), 2 Head, Department of Dermatology, Basel University Hospital, Basel, Switzerland. like cheek biting (), is usually a bad 3 Private Practice, Spalenpraxis Dermatology, Missionsstrasse 28, CH-4055 Basel, Switzerland. habit and may be evidence of psychologic stress or a

Correspondence: Dr Irène Hitz Lindenmüller, Department of Oral Sur- compulsive disorder. gery, Oral Radiology and Oral Medicine, School of Dental Medicine, Clinical features are chapped lips with a rough, University of Basel, Hebelstrasse 3, CH-4056 Basel, Switzerland. Email: [email protected] dehydrated, and occasionally edematous vermilion

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zone (Fig 2). Furthermore, cheilitis simplex can present mediated by an antigen-specific, -mediated, with severe scaling, ie exfoliative form (Fig 3), erosion, delayed-type hypersensitivity reaction (Type IV according and fissuring. These changes are often burning, itching, to the Gell-Coombs classification). On primary contact and painful. with the antigen, a sensitization phase of at least 5 days is Differential diagnosis should include cheilitis due to required. When an individual has already been sensitized contact allergy or toxic irritants and atopic cheilitis. In previously, the allergic reaction can develop far more elderly patients also (Fig 4) must be quickly, within a few hours to a few days. The clinical pic- considered. ture presents with dryness of the lips, scaling, and fissur- Cheilitis simplex can benefit from short-term use of ing. In more severe cases also and of the glucocorticoid ointments. To prevent recurrences, rig- lips, blistering, exudation, and crusts may be seen (Fig 6). orous lubricating lip care is crucial. Ointment bases, fragrances, preservatives, antioxi- dants, and dyes should be considered as possible trig- gers of allergic contact cheilitis. For women who use LIP-LICKING ECZEMA (LIP-LICKING nail polish, the polish ingredients (especially formalde- CHEILITIS) hyde) may be the cause for allergic contact cheilitis. Habitually licking the upper or lower lip with the Drug-related triggers are topical antibiotics, virostatic tongue or constantly sucking the lips inwards gives rise agents, disinfectants, local anesthetics, and sun protec- to lip-licking cheilitis. Typically, children are affected, tion filters. The most frequent allergens in 146 tested especially those with atopic dermatitis. Repeatedly patients with cheilitis were fragrances (cinnamalde- wetting the lips provides temporary relief for the feel- hyde, oakmoss, and isoeugenol), shellac, colophonium, ing of uncomfortable tightness of the lips, but in fact and Balsam of Peru.4 The triggering allergen was found further enhances the cheilitis. in lipsticks or other lip care products in half of the The typical feature is a sharply demarcated, brown- patients. Causative contact allergens can also be con- ish-red erythema pronounced at the margin, which tained in toothpastes, mouthwashes, and dental extends beyond the vermilion zone but remains con- impression materials. Allergic cheilitis is occasionally fined to the area of the skin that can be reached by the observed with food allergies, such as allergies to eggs tongue or the opposing lip.3 If lip-licking eczema per- or crustaceans.5 Contact allergies due to metals and sists for a prolonged period, it may be accompanied by woods from wind instruments and due to everyday scaling, crusting, and fissuring (Fig 5). Occasionally, objects that are held in the lips (eg, nails, needles, or secondary due to Candida and Staphylococ- ballpoint pens) should not be overlooked.3 cus aureus or streptococci may occur. Zug et al6 retrospectively evaluated the patch test- The success of treatment depends on a sustained ing of 196 patients with isolated lip dermatitis. An aller- change of behavior and a regular lubricant treatment. gic pathogenesis was verified in 75 cases (38%). In This form of eczema will clear up permanently if the addition to the aforementioned allergens, this study sufferer is able to give up the lip-licking habit. In the also found nickel to be a significant allergen. Schena et case of superinfection, topical antifungal or antibiotic al5 achieved similar results. They studied 129 patients therapy may be indicated. with chronic eczematous cheilitis and patch testing revealed a relevant sensitization in 65% of cases, espe- cially to metals (nickel, chromates, and manganese ALLERGIC CHEILITIS (ALLERGIC salts), fragrances, Balsam of Peru, and neomycin sulfate. CONTACT ECZEMA) Atopic cheilitis was diagnosed in 19% of patients. Allergic cheilitis is an allergic contact eczema of the lips in Accurate medical history is crucial to make the diag- reaction to an exogenous substance. The reaction is nosis. The suspected diagnosis is confirmed by patch

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Fig 1 Cheilitis sicca during acne treatment with systemic reti- Fig 2 Cheilitis simplex with rough, dehydrated, reddened lips noids. with scaling and fissures.

Fig 3 Exfoliative cheilitis with severe desquamation, fissures, Fig 4 Actinic cheilitis due to chronic light damage with redness, and edema of the lip vermilion. of the lip , , erythema, and blurred of the lower lip and erosion of the upper lip.

Fig 5 Lip-licking eczema with symmetrical, sharply defined Fig 6 Allergic cheilitis with papulovesicles, erythema, and edema erythema pronounced at the margin, with crusting, scaling, and of the lips. fissuring.

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testing. Identification followed by strict avoidance of CHEILITIS GLANDULARIS the causative allergen is imperative for successful treat- ment. As a supportive measure, a topical steroid may Cheilitis glandularis is a rare condition with inflamma- be used for a few days. tory change and hyperplasia of the minor salivary glands located in the lips. Usually only the lower lip is affected. The clinical picture consists of . CHEILITIS IN ATOPIC DERMATITIS The openings of the excretory ducts of the minor sali- Lip involvement is common in cases of atopic dermati- vary glands in the area of the lip margin and the adja- tis (Fig 7). Atopic cheilitis manifests as cheilitis sicca or cent lip mucosa are dilated and appear as miliary, exfoliative cheilitis and often as lip-licking eczema in transparent to dark red blister-like bulges.3 Shot grain- children. If the cheilitis persists for a prolonged period, like indurations can be palpated deep inside the lip. lichenification (coarse thickening) of the lips will occur In cheilitis glandularis simplex, a thick, mucoid, vis- as it does on the rest of the skin. Atopic cheilitis may cous, sticky saliva can be obtained by manual expres- also present with increased radial wrinkling of the lips sion. In the case of superinfection by staphylococci, the (Fig 8), with fissuring, and with perlèche cheilitis (angu- expressed material is purulent. The suppurative form is lus infectiosus). Perlèche cheilitis is one of the diagnos- subdivided into a superficial variant, cheilitis glandu- tic minor criteria for atopic dermatitis.7 laris purulenta superficialis, and a deep variant, cheilitis glandularis apostematosa.9 The etiology is uncertain. Swerlick and Cooper10 considered chronic irritation GRANULOMATOUS CHEILITIS (actinic, atopic, or mechanical) of the lower lip to be (SYNONYM: OROFACIAL causal and the chronic , ductal metaplasia, GRANULOMATOSIS) and fibrosis observed by histology to be secondary. In Chronic granulomatous inflammation of the lips can fact, the lip epithelium had frequently suffered actinic occur in isolation as Miescher’s granulomatous cheilitis damage in the cases that underwent histologic exami- or as part of granulomatous systemic diseases, in par- nation.9 Cheilitis glandularis is regarded as a premalig- ticular with Melkersson-Rosenthal syndrome (MRS), nant condition, with a few reported cases of develop- Crohn’s disease, and sarcoidosis. The clinical features ment of .9 are asymmetrical, painless, initially intermittent, later permanent, diffuse, tough, firm, elastic swelling of the LICHEN PLANUS lips, especially of the upper lip, and the surrounding skin (Fig 9). A median fissure of the lip and angular chei- Lichen planus (LP) is a chronic mucocutaneous disease litis may frequently be present. of uncertain etiology. It is a common condition and MRS is characterized by a triad of symptoms: granu- affects about 0.2% to 2% of the population. Adults lomatous cheilitis, facial palsy, and . aged between 40 and 70 years are typically affected.11 However, the complete triad only appears in about On the mucosae, a distinction is made between reticu- 25% of all MRS cases. Monosymptomatic or oligosymp- lar, leukoplakic, and erosive/ulcerative LP. Reticular LP tomatic forms are more common.8 is the most common type. It frequently affects the buc- The combination of granulomatous cheilitis with cal mucosa symmetrically. Tongue and gingiva are persistent intraoral aphthae may be indicative for often affected. Lip involvement is observed in about Crohn’s disease. 6% of cases.11 Reticular, striate, or annular Wickham The differential diagnosis of granulomatous cheilitis striae, patchy erythema, and occasionally erosions must include tuberculosis. appear on the lips, especially the lower lip (Fig 10). Like atopic dermatitis, LP can affect the lips in isolation.12

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Fig 7 Lip eczema and in atopic dermatitis. Fig 8 Increased radial wrinkling of the lip vermilion in atopic cheilitis.

Fig 9 Melkersson-Rosenthal syndrome with granulomatous Fig 10 Lichen planus of the lower lip with reticular and annular cheilitis, lip rhagades, and fissured tongue. Wickham striation and hemorrhagic, encrusted erosion.

Differential diagnosis should include a lichenoid drug ditis, endocarditis, and glomerulonephritis are classic reaction (especially caused by nonsteroidal anti-inflam- organ manifestations of SLE. On the lips, LE commonly matory drugs [NSAIDs], angiotensin-converting-enzyme manifests in its chronic discoid form or as diffuse cheili- [ACE]-inhibitors, antimalarial drugs, and gold), lichenoid tis. Both nearly always extend beyond the vermilion contact (mainly in response to amalgam and zone (unlike LP of the lips which in most cases is strictly other dental alloys), and discoid lupus erythematosus. confined within the vermilion borders). Anti-inflammatory treatment with corticosteroids The oral LE correlate with the specific lupus and/or tacrolimus as an ointment is very effective for manifestations on the skin and should be classified treating LP of the lips. accordingly.13 Three forms of the disease are identified.

Discoid LE or chronic cutaneous LE LUPUS ERYTHEMATOSUS Oral lesions appear in 3% to 20% of patients with dis- Lupus erythematosus (LE) is a chronic, episodic autoim- coid LE (DLE).14 Sharply defined, reddened, scaling, mune disease. It may affect only the skin or manifest hyperkeratotic, indurated plaques with a strong ten- itself as a systemic disease. Systemic LE (SLE) can dency to scarring are found on the skin. The scarring involve the visceral organs, the nervous system, and center often displays areas of depigmentation, hyper- the musculoskeletal system. Arthritis, pleurisy, pericar- pigmentation, and telangiectasia (Fig 11). On the

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Fig 11 Discoid lupus erythematosus with involvement of the Fig 12 Discoid lupus erythematosus of the buccal mucosa with lips; severe scarring with areas of depigmentation. sharply defined erythema with telangiectasias and radiating keratotic striae.

Fig 13 Mucosal manifestation on the hard in systemic Fig 14 Butterfly rash in acute systemic lupus erythematosus with lupus erythematosus. involvement of the lip vermilion. mucosa, DLE presents as irregularly bordered erythema can be seen. In more severe generalized with telangiectasia, atrophy, or ulceration, from which SCLE, lip involvement may result in diffuse erythema- radiating keratotic striae emanate (Fig 12). Unlike oral tous, scaling plaques that extend beyond the vermilion LP, the appearance of oral LE is usually asymmetric. In a onto the adjacent skin. recently published study15 involving 21 patients with oral DLE, 10% had isolated oral lesions while 90% also Systemic LE exhibited skin lesions at the same time. The labial Nine percent to 45% of patients with systemic LE (SLE) mucosa was involved in 76% of the patients, the lip show some oral involvement14 comprising circum- vermilion in 71%, and the buccal mucosa in 43%. In oral scribed or diffuse erythema, purpuriform macules, ero- and labial lupus, as with its cutaneous counterpart, sions, and ulcerations for which the favored site is the there is an increased risk of developing squamous cell hard palate (Fig 13). The oral ulcers are specific lupus carcinoma if prolonged, scarred lesions are present. lesions which are regarded as a major criterion for SLE diagnosis. A generalized acute lupus rash in SLE may Subacute cutaneous LE also involve the lips in some cases (Fig 14). Lupus on the Subacute cutaneous LE (SCLE) is often induced or lips can be clinically confused with contact allergic chei- aggravated by UV exposure. Oral manifestations are litis, actinic cheilitis, LP, psoriasis, , rare. Sharply defined, slightly atrophic erythema of the vulgaris, and squamous cell carcinoma.

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Fig 15 Angioedema of the upper lip.

Angioedema (AE)

AE with urticaria AE without urticaria

Drug-related Immediate-type Hereditary or • ACE inhibitor allergy, NSAID intolerance Idiopathic AE acquired C1 • Angiotensin I IgE-mediated inhibitor defi ciency receptor inhibitor

Mediator: Mediator: Mediator: bradykinin histamine leukotrienes

Fig 16 Angioedema – diagnostic algorithm.

ANGIOEDEMA (SYNONYMS: lives. Angioedema often accompanies urticaria. It is QUINCKE’S EDEMA, seen with immediate-type allergy, intolerance reaction ANGIONEUROTIC EDEMA) to foods or drugs, or contact allergy such as to latex. Isolated angioedema as an expression of a hereditary or The term angioedema denotes acute, transient, often acquired C1 esterase inhibitor defi ciency is less com- massive swelling that particularly aff ects the lips mon. (Fig 15), the lid region, face, genitalia, and/or the The fi rst diagnostic step is to diff erentiate angio- mucosa of the upper airways and the gastrointestinal edema with urticaria from angioedema without urti- tract. Edema of the glottis can be life-threatening. caria16,17 because these two forms are based on a very Angioedema is a common problem, aff ecting one in diff erent pathogenesis, which results in a diff erent four to one in fi ve people during the course of their therapeutic approach (Fig 16). Histamine-mediated

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Table 1 Causes of macrocheilia

Timescale Etiology Disease Congenital • Hereditary angioedema • Hematoma Trauma • Emphysema • Lip abscess, furuncle • Erysipelas • labialis Temporary lip swelling Infection • Syphilis • Leprosy • Tuberculosis • Leishmaniasis • Granulomatous cheilitis in initial stage Other • Allergic or idiopathic angioedema • Insect bite or sting • Idiopathic-familial • Vascular malformations (Sturge-Weber syndrome) • Ascher’s syndrome (double lip) Congenital • Down syndrome • Multiple endocrine neoplasia syndrome MEN type 2B (labial neuromas) • Storage diseases • Vascular tumors (lymphangioma, hemangioma) Permanent lip enlargement • Tumors • Pseudolymphoma • Neurofibroma • Leukemia • Cheilitis glandularis • Sarcoidosis Other • Acromegaly • Myxedema

angioedema is treated with systemic antihistamines MACROCHEILIA and corticosteroids. By contrast, antihistamines and corticosteroids are not effective in bradykinin-mediated Enlargement of one or both lips has adverse cosmetic angioedema.17 In hereditary angioedema and acquired and functional effects. The causes are many and varied. C1 esterase inhibitor deficiency, the administration of Transient or temporary lip swelling must be distin- C1 inhibitor is required. This should also be given pro- guished from chronic, permanent lip enlargement phylactically when there is specific exposure, eg prior (Table 1). Angioedema is the most common cause of to dental treatments.18 transient macrocheilia. Granulomatous cheilitis in its iso- lated form as Miescher’s cheilitis or in the context of MRS is the most common cause of chronic macrocheilia.19

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