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Home , Actinic cheilitis, Angular cheilitis, Cheilitis, Noma (disease), Oral allergy syndrome

Acta Clin Croat 2018; 57:342-351 Review doi: 10.20471/acc.2018.57.02.16

DIFFERENTIAL DIAGNOSIS OF – HOW TO CLASSIFY CHEILITIS?

Liborija Lugović-Mihić1,2, Kristina Pilipović2, Iva Crnarić1, Mirna Šitum1,2 and Tomislav Duvančić1

1Department of Dermatovenereology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia; 2School of Dental Medicine, University of Zagreb, Zagreb, Croatia

SUMMARY – Although cheilitis as a term describing infl ammation has been identifi ed and recognized for a long time, until now there have been no clear recommendations for its work-up and classifi cation. Th e may appear as an isolated condition or as part of certain systemic /

conditions (such as due to B12 or defi ciency) or local (e.g., herpes and oral ). Cheilitis can also be a symptom of a contact reaction to an irritant or , or may be provoked by sun exposure () or drug intake, especially . Generally, the forms most commonly reported in the literature are angular, contact (allergic and irritant), actinic, glandular, granulomatous, exfoliative and plasma cell cheilitis. However, variable nomenclature is used and sub- types are grouped and named diff erently. According to our experience and clinical practice, we suggest classifi cation based on primary diff erences in the duration and etiology of individual groups of cheili- tis, as follows: 1) mainly reversible (simplex, angular/infective, contact/eczematous, exfoliative, drug- related); 2) mainly irreversible (actinic, granulomatous, glandular, plasma cell); and 3) cheilitis con- nected to dermatoses and systemic diseases (lupus, , / group, , , etc.). Key words: Cheilitis; Infl ammation; Lip Diseases; Actinic Cheilitis; Classifi cation; , Contact

Introduction lated to the eff ects of irritants (climatic, mechanical, caustic agents) or (allergic contact cheilitis)5. Th e term ch eilitis indicates infl ammation of the lip and includes many types, i.e. angular, contact, exfolia- Some types of cheilitis last longer and are persistent, tive, actinic, glandular, granulomatous, plasma cell such as chronic actinic cheilitis, granulomatous cheilitis, simplex, etc.1-5. In practice, it is diffi cult to de- cheilitis and plasma cell cheilitis. Furthermore, cheili- fi ne readily the precise type of cheilitis, thus proper tis can also be seen in various skin or systemic diseases diagnostic procedures are necessary to determine the such as , lichen planus, atopic exact disease based on its characteristics5. For example, dermatitis, etc. can occur spontaneously or may be Cheilitis may also be associated with numerous related to several precipitating factors (e.g., systemic conditions or diseases, e.g., nutritional defi ciencies, immune suppression, local irritation and moisture, such as due to defi - fungal/bacterial ). Contact cheilitis can be re- ciency, anemia due to iron defi ciency, , diabetes2,4-8. Correspondence to: Prof. Liborija Lugović-Mihić, MD, PhD, De- Additionally, cheilitis is often divided into particu- partment of Dermatovenereology, Sestre milosrdnice University lar subtypes with no clear classifi cation having yet Hospital Center, Vinogradska c. 29, HR-10000 Zagreb, Croatia E-mail: [email protected] been adopted. Considering its duration, some authors Received August 28, 2017, accepted December 12, 2017 refer to or chronic cheilitis, whereby there are no

342 Acta Clin Croat, Vol. 57, No. 2, 2018 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis

Table 1. Proposed classifi cation of cheilitis In association with dermatoses and systemic Mostly reversible Mostly persistent diseases (common diseases) Cheilitis simplex Actinic cheilitis Lupus erythematosus Angular/infective cheilitis Granulomatous cheilitis Lichen planus Contact/eczematous cheilitis Glandular cheilitis Angioedema Exfoliative cheilitis Plasma cell cheilitis Pemphigoid/pemphigus Drug related cheilitis Xerostomia multiforme Crohn’s disease Sarcoidosis, etc.

Table 2. Prominent features of mostly reversible cheilitis Mostly reversible Occurrence Related factors Th erapy cheilitis Cheilitis simplex Common Lip licking Advice on environmental conditions Cold, windy, dry weather Application of lip balms, petroleum jelly, emollients, topical , ointments Angular/infective Common Infective agents Elimination of local predisposing cheilitis Immune defi ciency (, HIV) factors Mechanical factors Topical antimycotics, antiseptics, Nutritional defi ciencies , topical corticosteroids (ribofl avin, , iron, etc) Contact/eczematous Very common , contact allergens/irritants Topical corticosteroids (low to cheilitis medium potency), emollients Exfoliative cheilitis Rare Lip licking/picking Corticosteroids Psychological distress Psychotherapy Nutritional defi ciencies (some cases resolve spontaneously) Drug related cheilitis Rare Drugs Emollients Drug elimination if possible clear criteria2. Although there are many recent papers Reversible Cheilitis on cheilitis, they are mostly case reports and overviews of therapeutic or diagnostic procedures based on per- We specify reversible cheilitis (transitory cheilitis sonal experiences and results without specifi c criteria of temporary duration) as a distinct category, which for classifi cation. Since clear classifi cation has not yet includes several subtypes (Table 2). been established, there are no defi nitive recommenda- Cheilitis simplex (chapped , common cheilitis, tions for diagnosing all diff erent types of cheilitis. cheilitis sicca) is one of the most common subtypes, Apart from that, cheilitis is also a disease that requires presenting as cracked lips, fi ssures or desquamation of a multidisciplinary approach, which additionally the lips, usually of the lower lip (Fig. 1)2,7. Here fre- complicates adoption of a classifi cation system. We quent lip licking promotes dryness and irritation, end- would like to put forth a classifi cation of cheilitis into ing in separation of the mucosa and cracking. Some three main groups with further particular subtypes authors use a diff erent label for a similarly categorized (Table 1). subtype, lip licking cheilitis, due to lip licking habit or

Acta Clin Croat, Vol. 57, No. 2, 2018 343 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis

Fig. 1. Cheilitis simplex. Fig. 2. Contact/eczematous cheilitis. frequent lip retraction into the oral cavity (especially in tain drug therapy (e.g., ), and somewhat children with )6,7. Such licking re- less frequently in primary . It is moves the thin, oily surface fi lm that protects the lips more common during winter when additional lip lick- from moisture loss, leading to lip cracking. Lip ing worsens the condition, and in elderly persons2,5. It are also infl uenced by , the digestive enzymes of can occur in patients with infl ammatory bowel dis- which can irritate the lips by extracting moisture and eases such as Crohn’s disease and ulcerative colitis10. causing evaporation. Some children have the habit of Th is subtype sometimes develops as part of a group sucking and biting the lower lip, whereby a sharply of symptoms, which can include atrophic , bordered perioral erythema may occur. esophageal webs or strictures, and microcytic hypo- Diff erential diagnosis includes contact cheilitis, chromic anemia (Plummer-Vinson syndrome)11. Con- atopic cheilitis, actinic cheilitis, etc.2,4. Th erapy mostly currence of bacterial or candidal infection (primary or involves advice on dealing with environmental condi- secondary) is common2. Children, especially those tions and the application of lip balms, petroleum jelly, with atopic dermatitis, are most commonly aff ected by emollients and sometimes topical corticosteroids, secondary bacterial infections (staphylococcal and be- mostly low potency ointments. ta-hemolytic streptococcal) on damaged lip corners. Angular cheilitis (also termed perleche, cheilosis, or Angular cheilitis with secondary infections often oc- angular or angulus infectiosus) typically curs also in patients with (congenital hy- manifests at the corners of the /lips. Th e disease pothyroidism and ). is most common in patients with deep wrinkles in lip Diff erential diagnosis for this type of cheilitis in- angles and those who are prone to licking lip corners8. cludes recurrent (if lesions are unilater- Generally, the disease starts during vitamin and min- al) and secondary (fi ssured papules at the cor- eral defi ciencies (B , iron, zinc, etc.), or is ners of the lips similar to cheilitis)2,9. Th erapy includes caused by other conditions and diseases (e.g., poorly elimination of predisposing factors and often topical fi tting and , celiac disease)4,6,9. An antimycotics, antiseptics, antibiotics, and sometimes important factor is also saliva production, i.e. increased corticosteroids. secretion and drooling, which contributes to the dis- Contact/eczematous cheilitis is an infl ammatory lip ease. Conversely, during decreased saliva secretion (hy- reaction caused by the irritating or allergic eff ects of posalivation), dryness promotes cracking and desqua- various substances found in many products such as lip- mation, as well as the invasion of albicans with sticks, products (toothpastes), food (e.g., the emergence of angular cheilitis infl ammation. eggs and crustaceans), ointment bases, fragrances, pre- Angular cheilitis occurs more commonly in diabet- servatives, antioxidants, dyes, dental materials, musical ics, in patients with some psychiatric disorders (e.g., lip or occupational instruments, objects put in the mouth trauma in bulimics or in ), during cer- daily (e.g., nails, needles, pens), etc.7,12. It manifests as

344 Acta Clin Croat, Vol. 57, No. 2, 2018 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis dryness, scaling, erythema or fi ssuring, more common- liative cheilitis presents with continuous peeling of the ly on the skin than on mucosa (Fig. 2)2,13,14. Th is type of vermilion (lip border). Initially, lips may usually look cheilitis usually presents in patients with atopic der- normal or red, followed by development of a thickened matitis15. Some authors use the term cheilitis venenata, surface layer, which leads to peeling that may be cyclic which specifi cally indicates contact reaction, most and proceeds at diff erent rates and at diff erent sites. commonly of an allergic type. Sometimes bleeding occurs, later followed by the for- Th ere is a broad spectrum of products with com- mation of a hemorrhagic crust. Th e disease may prog- mon irritants and allergens associated with this sub- ress due to several factors, e.g., open-mouthed breath- type. Contact reactions to lipsticks, rubber, leather ob- ing, lip licking, sucking, picking, or biting, bacterial jects, nail polish substances (e.g., formaldehyde), met- () or yeast () in- als (nickel, cobalt, gold) and topical antibiotics have fection, poor oral hygiene, etc.1. Some use the term been shown to be some of the more frequent etiologic exfoliative cheilitis as an equivalent to cracked lips, factors7,12. Reactions to compounds in topical medica- which increases confusion around nomenclature. tions and medical products, such as topical antibiotics, Diff erential diagnosis includes contact cheilitis, virostatic agents, disinfectants, local anesthetics, and cheilitis simplex, etc. Th erapy includes topical cortico- are also possible. Factitial cheilitis stands steroids, topical calcineurin inhibitor, topical Calen- out as a distinct subtype of contact cheilitis, usually dula offi cinalis L., and in some cases psychotherapy1,18. triggered by a stressful event (possible self-damaging Occasionally, lesions resolve spontaneously. behavior). Drug-induced cheilitis refers to lesions due to drug Use of the is important to determine intake, mainly retinoids (e.g., isotretinoin, acitretin) or these cheilitis causing allergens and to identify the other medications (topical antibiotics, virostatic agents, etiologic allergen7. Patch testing usually starts with the lip care products, disinfectants, local anesthetics, European baseline series and an overview of the pa- creams with protection factors, etc.)19. Also possible tient’s personal cosmetic and topical products, the re- are drug reactions on skin and lips, in the form of li- sults of which mostly reveal contact allergens3. Ac- chenoid reactions, fi xed drug eruptions, or changes re- cording to recent patch testing results in patients with sembling erythema multiforme2,19. Emollients are cru- non-actinic cheilitis, reported by O’Gorman and cial in the treatment, and discontinuation of the of- Torgerson, the most signifi cant allergens were fra- fending agent when possible. grance mixes, Myroxilon pereirae resin, dodecyl gallate, 13 octyl gallate, and benzoic acid . According to these Irreversible Cheilitis results, relevant allergens in those patients were fra- grances, antioxidants, preservatives and metals (nickel Th is group contains a number of chronic cheilitides and gold). the verifi cation of which usually calls for and Diff erential diagnosis of contact/eczematous chei- histology (Table 3). litis includes cheilitis simplex, exfoliative cheilitis, Actinic (solar) cheilitis (actinic cheilosis, sailor’s lip) among other types of cheilitis. In the treatment, most (Fig. 3) is damage to the lower lip and considered to be important is to exclude etiologic factors. Th erapy in- a potentially malignant disorder. It is caused primarily cludes mostly topical corticosteroids of low to medium by exposure to radiation, thus it is common- potency and emollients, which may be combined. ly found in certain groups of workers (sailors, agricul- Exfoliative cheilitis indicates lip infl ammation, ac- tural workers, construction workers, beach workers, companied by constant desquamation, more common- etc.)20-24. When erosions are a predominant symptom ly found on just one lip, usually the lower one. Th is of the condition, then the term cheilitis abrasiva prae- form occurs a bit less frequently than others, and is cancerosa is used. common among young people who frequently mois- Th is disease occurs mostly in middle-aged, fair- turize their lips, followed by people with vitamin B12 or skinned men and is a potentially malignant condition iron defi ciency, oral candidiasis, patients with that requires to exclude severe dysplasia or (e.g., to balsam of Peru) or patients with HIV in whom cancer5. Clinically, the disease manifests with painless it is often associated with candida infection16-18. Exfo- thickening and whitish discoloration at the borders of

Acta Clin Croat, Vol. 57, No. 2, 2018 345 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis

Table 3. Common features of mostly persistent cheilitis Mostly persistent Occurrence Related factors Th erapy cheilitis Actinic cheilitis Rare Sun damage Topical low to medium potency (outdoor workers, corticosteroids or 5-fl uorouracil, chemical peel middle-aged fair-skinned men) cryotherapy, electrosurgery, vermilionectomy, immunosuppressants, and surgery Granulomatous Rare Other granulomatous diseases Topical, intralesional (e.g., repeated cheilitis acetonide 2.5-5.0 mg/mL) and systemic corticosteroids and/or antibiotics Glandular cheilitis Very rare , poor oral hygiene, Systemic antibiotics and topical, intralesional external infl uences () or systemic corticosteroids, or surgical excision Plasma cell cheilitis Very rare Unknown Topical and intralesional corticosteroids, destructive measures, or sometimes even immunosuppressants the lips and skin. Consequently, the lip border (vermil- ion border) becomes less clear and the lips may gradu- ally become scaly and indurated. Th e lesions are usu- ally persistent and therefore require biopsy for disease verifi cation. Histopathologically, epithelial oc- curs fi rst without cytologic atypia but with solar elas- tosis of adjacent skin, while later squamous cell carci- in situ develops with cytologic atypia, epithelial atrophy or hyperplasia, followed by strands of epithe- lium growing down into the lamina propria2. Th ere- fore, severe dysplasia is characterized by dyskeratosis and keratin pearls, nuclei changes (hyperchromasia, nuclear pleomorphism, anisonucleosis, increased num- Fig. 3. Actinic cheilitis (a photo from ref. 23; bers of nucleoli and mitoses, atypical mitoses)25. Th ere with the author’s permission and by the courtesy are recent data that indicate, according to Fourier of Professor Mravak-Stipetić). transform infra red (FT-IR) spectroscopy, that chang- es in and nucleic acids could be used as mo- lecular biomarkers for malignant transformation20. etiology, which usually starts in young adults and pres- Diff erential diagnosis of actinic cheilitis includes a ents with intermittent or permanent lip swelling (Fig. number of diseases, i.e. epithelial dysplasia, squamous 4)5,26-28. Th e cause of granulomatous cheilitis has not cell carcinoma, malignant melanoma, basal cell carci- yet been fully elucidated, but current hypothesis holds noma, , glandular cheilitis, herpes la- that random infl ux of infl ammatory cells is responsi- bialis, discoid lupus erythematosus, etc. Th erapy is re- ble. Other proposed related factors of the disease in- quired to relieve symptoms and to prevent develop- clude dietary allergens such as cinnamon and benzo- ment of squamous carcinoma. It includes topical low ates26. to medium potency corticosteroids, 5-fl uorouracil, Th e disease can occur as Miescher’s isolated granu- chemical peel, cryotherapy, electrosurgery, vermilion- lomatous cheilitis or with other granulomatous dis- ectomy, immunosuppressants, surgery, and also sun- eases (Crohn’s disease, sarcoidosis and Melkersson- screens (sun protection). Rosenthal syndrome)5,7. Melkersson-Rosenthal syn- Granulomatous cheilitis (or orofacial granulomato- drome is characterized by granulomatous cheilitis, fa- sis) is chronic granulomatous lip swelling of unknown cial palsy and plicated tongue, although only one or

346 Acta Clin Croat, Vol. 57, No. 2, 2018 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis

gradually evolving lip (). It can be related to chronic irritation of the lower lip (actinic, atopic or mechanical), with potential secondary causes being chronic , ductal metaplasia and fi bro- sis. Glandular apostematosa cheilitis is a secondary staphylococcal infection of the minor salivary glands, which presents with crust and drainage accompa- nied by pain. Histopathology is nonspecifi c with possible sali- vary gland hyperplasia, duct ectasia, and dermal in- fl ammatory infi ltrate (lymphocytes, plasma cells, his- tiocytes). Diff erential diagnosis includes other forms of cheilitis and . Management Fig. 4. Granulomatous cheilitis. includes histopathologic analysis, identifi cation of eti- ologic factors, and attempts to alleviate or eradicate two symptoms usually appear (the complete triad of these factors. Th erapy includes systemic antibiotics symptoms occurs in only 25% of patients). Granulo- and topical, intralesional or systemic corticosteroids, or matous cheilitis accompanied by persistent intraoral surgical excision. aphthae may suggest Crohn’s disease. Plasma cell cheilitis is a very rare type of lip infl am- Histologically, granulomatous cheilitis is charac- mation of unknown etiology characterized histologi- terized by chronic infl ammatory reaction consisting of cally by diff use plasma cell infi ltration in dermis27,30. lymphocytes, histiocytes, and tuberculoid granuloma Clinically, it presents as a circumscribed and fl at to having epithelioid cells and Langerhans giant cells27. slightly raised eroded area of the lip, or as erythema- Histology from early lesions shows only edema and tous-violaceous, ulcerated and asymptomatic plaques sparse infi ltrate, while later there is a more intense in- which evolve slowly. Histology includes a band-like fi ltrate with small sarcoidal granulomas. Diff erential infi ltrate of plasma cells in the upper dermis, with pos- diagnosis of granulomatous cheilitis includes elephan- sible capillary dilation, erythrocyte extravasation, he- tiasis nostras, forms of recurrent erysipelas and herpes mosiderin deposits, and mild epidermal spongiosis. simplex, macrocheilia, angioedema, tuberculosis, glan- Diff erential diagnosis includes actinic cheilitis, allergic dular cheilitis, contact cheilitis, Ascher’s syndrome, or- contact cheilitis, lichen planus, etc. Th erapy may in- ganized hematoma, sarcoidosis, among others14,26,27. clude topical and intralesional corticosteroids, topical Th erapy may include topical, intralesional (e.g., triam- calcineurin inhibitors, destructive treatment methods, 30 cinolone acetonide 2.5-5.0 mg/mL for several months or sometimes even immunosuppressants . or longer) and systemic corticosteroids/antibiotics, di- etary modifi cations and surgery, although treatment is Cheilitis Associated with Skin Diseases 26,28 not always necessary . and Systemic Diseases Glandular cheilitis is a rare chronic infl ammatory condition of the minor salivary glands, predominantly Th e chronic discoid form of lupus erythematosus can of the lower lip2,29. Th e disease was fi rst described by sometimes encompass lip changes/lesions, which pres- von Volkmann under the designation ‘cheilitis glandu- ent as diff use cheilitis, spreading usually above the ver- laris apostematosa’ or ‘myxadenitis labialis’29. Etiologic milion zone. Subacute cutaneous lupus erythematosus factors considered to be involved are smoking, poor rarely includes oral lesions, manifesting with sharply oral hygiene, chronic exposure to external infl uences bordered, slightly atrophic erythema of or, (sunlight, wind, tobacco), bacterial infection and con- as in severe cases, a diff use erythematous, plaque, genital predisposition. which extends beyond the vermilion. Lip changes in Variants are cheilitis simplex and cheilitis apostema- systemic lupus erythematosus may present as bordered tosa. Th e simplex form usually manifests as tiny red or diff use erythema, purpuric maculae, erosions or ul- papules, especially on the lower lip, with a possible, cerations, or patients may have oral ulcerations, which

Acta Clin Croat, Vol. 57, No. 2, 2018 347 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis

Fig. 5. Lip lesions/cheilitis in association with pemphigus Fig. 6. Lip lesions/cheilitis in association with erythema vulgaris. multiforme. are one of the major criteria for systemic lupus erythe- Lips may also be aff ected as part of other dermato- matosus diagnosis31. Generalized in acute lupus ses, e.g., (Fig. 6), atopic dermati- can also aff ect the lips in some cases. Diff erential diag- tis, , Stevens-Johnson syndrome, and nosis of lupus erythematosus on the lips may include toxic epidermal necrolysis, often resulting in the for- allergic , actinic cheilitis, lichen pla- mation of erosions and crusts2,19. nus, psoriasis, erythema multiforme, pemphigus vul- garis, squamous cell carcinoma, etc. Discussion Lichen planus as a chronic mucocutaneous disease occurs in 6% of cases on the lips in the form of reticu- Cheilitis is a term describing lip infl ammation of lar, striatus or annular Wickham’s striae, irregular various etiologies, which occurs relatively often. Th e (patchy) erythema and erosions, especially of the lower disease may appear as an isolated condition or as part lip32. Diff erential diagnosis includes lichenoid drug re- of certain systemic diseases or conditions. It may be actions (e.g., to antiinfl ammatory medications, angio- part of a clinical picture or an accompanying condi- tensin-converting enzyme inhibitors, antimalarials), tion. Cheilitis can co-occur with many conditions in- lichenoid contact dermatitis (e.g., to amalgam and cluding anemia, oral candidiasis, atopy, contact reac- other dental materials), discoid lupus erythematosus, tion to an irritant or allergen (e.g., to cosmetics), drug etc. intake (e.g., retinoids), etc. Generally, the most com- Angioedema manifests often on the lips and is monly reported forms in the literature are angular, mostly allergic19,33. It is one of the most common contact (allergic and irritant), actinic, exfoliative, causes of transient lip swelling, while macrocheilia de- etc.2,21-24. As contact cheilitis can be related to the ef- scribes permanent swelling of one or both lips. fects of irritants or allergens, it should be investigated Manifestations of bullous diseases are also possible with thorough history taking. Some lip lesions require on the lips, especially in pemphigus vulgaris (Fig. 5), an biopsies, such as chronic actinic cheilitis (to examine autoimmune mucocutaneous blistering disease the ini- for severe dysplasia or cancer) or granulomatous chei- tial manifestations of which often are oral lesions (50% litis (to confi rm the diagnosis)5,22,35. to 70% of cases), mostly erosions. Similar changes may When managing and diagnosing cheilitis, com- be seen in the pemphigoid group34. Sometimes it ini- plete examination of the patient’s oral cavity, skin and tially presents with single persistent lower lip lesions other mucosae is required, along with appropriate di- without progressing to other location. Both the pem- agnostic procedures. When approaching patients, sev- phigus and pemphigoid workups are complex and in- eral factors need to be taken into account, particularly clude histopathologic and immunofl uorescent diag- patient general medical history (e.g., existence of dia- nostics. betes, atopy, ), exposure to external

348 Acta Clin Croat, Vol. 57, No. 2, 2018 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis

Table 4. Common diagnostic parameters/procedures related to specifi c cheilitis group In association with Mostly persistent Mostly reversible dermatoses and (irreversible) systemic diseases – History data: drug intake, habits (lip licking, biting, sucking, picking, Persistent lesions Diagnostic etc.), weather conditions (cold, hot, windy, dry weather), age, poor oral require biopsy work-up according hygiene, open-mouthed breathing, related diseases/conditions and to suspected disease (e.g., diabetes, psychiatric disorders, atrophic glossitis, dysphagia, histopathologic esophageal webbing, etc.) analysis – Defi ciencies, e.g., (B2, B3, B5, B7, B12), iron, zinc, etc., (e.g., celiac disease), or hypervitaminosis (e.g., ) – Atopy (in patient and family): total IgE, allergic skin tests (patch test, prick test), in vitro allergic tests – Oral and skin swabs (mycotic and bacterial; e.g., yeast infection such as Candida albicans or bacterial infection such as Staphylococcus aureus or ) factors (e.g., weather conditions), the possibility of vi- due to an , toxin, medication or injury (eczema- tamin or mineral defi ciencies, undesirable habits (lip tous cheilitis, allergic contact cheilitis, pigmented con- licking, frequent sun exposure, lip contact with various tact cheilitis, cheilitis in musicians, contact reactions to substances), etc. (Table 4). It is also important to know lipsticks and other lipcare products, irritant and aller- whether the lesions are persistent or whether they are gic contact dermatitis, smoking and its eff ects on the reversible since irreversible cheilitis demands a diff er- skin, , isotretinoin treatment, acitretin treat- ent treatment approach. ment, denture stomatitis); and (3) cheilitis due to nu- Until now, there have been no clear recommenda- tritional defi ciency (iron, vitamin B)4. tions for the workup and classifi cation of cheilitis al- According to our experience and clinical practice, though cheilitis has been identifi ed and recognized for we suggest the classifi cation of cheilitis as (1) mainly quite a long time. In the literature on cheilitis, varied reversible (transient); (2) mainly irreversible (persis- nomenclature is used and subtypes are grouped and tent); and (3) cheilitis associated with particular der- named diff erently. Braun Falco et al., for instance, clas- matoses and systemic diseases (Table 1). Th is kind of sify cheilitides as angular, simplex, actinic (acute/ classifi cation would be based upon primary diff erences chronic), glandularis, granulomatous and plasma cell in the course and etiology of individual groups of chei- cheilitis2. According to the PUBMED/MEDLINE litides. Th us, the group of reversible cheilitides (of database, the total number of published articles re- temporary duration) includes mostly milder types of trieved by the keywords ‘cheilitis classifi cation’ does cheilitis, which usually signifi cantly regress following not exceed 14 while those searched by the keywords elimination of the etiologic factor. Rarely they are per- ‘diff erential diagnosis’ does not exceed 120. Regarding sistent and resistant to treatment. Cheilitides of the newly published articles, most are case reports and irreversible type have a more lasting character, which overviews of therapeutic or diagnostic procedures usually requires histologic workup (biopsy). Finally, based on personal experiences and results. Taking into the third class of cheilitides encompasses infl amma- account our experience and that of other authors, we tory lip changes related to specifi c skin or systemic dis- are off ering an overview of the most important cheili- eases. tis types. According to Oakley, there are few cheilitis Th ere are no precise epidemiologic data on the groups: (1) cheilitis due to infection or skin conditions prevalence and incidence of each cheilitis type either. (angular, granulomatous, , We can only give data on its frequency based on our Crohn’s skin disease, actinic, exfoliative, glandular, li- clinical experience. Th e approach to cheilitis needs to chenoid, cutaneous lupus erythematosus); (2) cheilitis be interdisciplinary and should include dermatolo-

Acta Clin Croat, Vol. 57, No. 2, 2018 349 Liborija Lugović-Mihić et al. Diff erential diagnosis of cheilitis gists, oral pathologists, ENT specialists, and also spe- 9. Park KK, Brodell RT, Helms SE. Angular cheilitis. Part 2: Nu- cialists in internal medicine and psychiatry1,6,7,10,19,26,36-39. tritional, systemic, and drug-related causes and treatment. Cu- Professionals from diff erent specialties can come to a tis. 2011;88:27-32. conclusive diagnosis by additional specifi c diagnostics. 10. Muhvić-Urek M, Tomac-Stojmenović M, Mijandrušić-Sinčić B. Oral pathology in infl ammatory bowel disease. World J Gas- It is important to have in mind that the approach to a troenterol. 2016;22:5655-67. doi: 10.3748/wjg.v22.i25.5655. patient with cheilitis includes, apart from dermato- 11. Samad A, Mohan N, Balaji RV, Augustine D, Patil SG. 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Sažetak

DIFFERENCIJALNA DIJAGNOZA HEILITISA – KAKO KLASIFICIRATI HEILITIS?

L. Lugović-Mihić, K. Pilipović, I. Crnarić, M. Šitum i T. Duvančić

Iako je heilitis kao pojam koji opisuje upalu usnica bio zapažen i prepoznat već prije dugo vremena, dosad nema jasnih preporuka za dijagnostički postupak i klasifi kaciju. Bolest se može javiti kao izolirano stanje ili kao dio nekih bolesti/stanja poput anemije (zbog nedostatka vitamina B12 i željeza) ili lokalne infekcije (npr. herpes i oralna kandidijaza). Heilitis također može biti simptom kontaktne reakcije na iritans ili alergen te može biti potaknut izlaganjem suncu (aktinički heilitis) ili uzimanjem lijeka (osobito retinoida). Općenito se najčešće spominju oblici angularni, kontaktni (alergijski i iritativni), akti- nički, glandularni, granulomatozni, eksfolijativni i plazmacelularni heilitis. Ipak se u literaturi o heilitisu rabi različita nomen- klatura pa su podtipovi grupirani i nazvani različito. Prema našem iskustvu i kliničkoj praksi predlažemo klasifi kaciju teme- ljenu na primarnoj razlici u trajanju i etiologiji pojedinih skupina heilitisa: 1. pretežno reverzibilni (simpleks, angularni/in- fektivni, kontaktni/ekcematoidni, eksfolijativni, lijekom potaknuti), 2. pretežno ireverzibilni (aktinički, granulomatozni, glandularni, plazmacelularni) i 3. heilitisi povezani s dermatozama i sustavnim bolestima (lupus, lihen planus, skupina pem- fi gusa/pemfi goida, angioedem, kserostomija itd.). Ključne riječi: heilitis; upala; usna, bolesti; aktinički heilitis; klasifi kacija; dermatitis, kontaktni

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