IN BRIEF • Cancer and some systemic diseases may present with ulceration. • Disorders of the blood, infections, gastrointestinal disease and skin diseases may cause mouth ulceration. • Biopsy or other investigations may be indicated. 2

Oral Medicine — Update for the dental practitioner. Mouth ulcers of more serious connotation

C. Scully1 and D. H. Felix2

This series provides an overview of current thinking in the more relevant areas of oral medicine for primary care practitioners, written by the authors while they were holding the Presidencies of the European Association for Oral Medicine and the British Society for Oral Medicine, respectively. A book containing additional material will be published. The series gives the detail necessary to assist the primary dental clinical team caring for patients with oral complaints that may be seen in general dental practice. Space precludes inclusion of illustrations of uncommon or rare disorders, or discussion of disorders affecting the hard tissues. Approaching the subject mainly by the symptomatic approach — as it largely relates to the presenting complaint — was considered to be a more helpful approach for GDPs rather than taking a diagnostic category approach. The clinical aspects of the relevant disorders are discussed, including a brief overview of the aetiology, detail on the clinical features and how the diagnosis is made. Guidance on management and when to refer is also provided, along with relevant websites which offer further detail.

ORAL MEDICINE MALIGNANT ULCERS erosions or ulceration (or occasionally blisters) 1. Aphthous and other A range of neoplasms may present with ulcers, include particularly Behcet’s syndrome, and a common ulcers most commonly these are carcinomas (Fig. 1), but number of skin diseases including lichen planus 2. Mouth ulcers of more Kaposi’s sarcoma, lymphomas and other neo- (Fig. 2; see Article 5), occasionally erythema multi- serious connotation plasms may be seen and are discussed in Article 9. forme or pemphigoid, and rarely pemphigus. 3. Dry mouth and disorders Most present with a single persistent ulcer. Biopsy of salivation is usually required to establish the diagnosis. BEHCET’S SYNDROME 4. Oral malodour Behcet’s syndrome (BS) is a rare condition. It is the SYSTEMIC DISEASE association of recurrent aphthous stomatitis 5. Oral white patches A wide range of systemic diseases, especially (RAS) with genital ulceration and eye disease, but 6. Oral red and mucocutaneous diseases, blood, gut, and miscel- other systemic manifestations may also be seen. hyperpigmented patches laneous uncommon disorders, may cause oral The disease is found worldwide, but most com- 7. Orofacial sensation and lesions which, because of the moisture, trauma monly in people from Eastern Mediterranean movement and infection in the mouth, tend to break down countries (particularly Greeks, Turks, Arabs and 8. Orofacial swellings and to leave ulcers or erosions. Most present with Jews) and along the Silk Route taken by Marco lumps multiple often persistent ulcers. Biopsy is often Polo across eastern Asia, China, Korea and Japan. 9. Oral cancer required to establish the diagnosis. 10. Orofacial pain Aetiopathogenesis MUCOCUTANEOUS DISORDERS Behçet’s syndrome is a vasculitis that has Mucocutaneous disease that may cause oral not been proved to be infectious, contagious or 1*Professor, Consultant, Dean, Eastman Dental Institute for Oral Health Care Sciences, 256 Gray’s Inn Road, UCL, University of London, London WC1X 8LD; 2Consultant, Senior Lecturer, Glasgow Dental Hospital and School, 378 Sauchiehall Street, Glasgow G2 3JZ / Associate Dean for Postgraduate Dental Education, NHS Education for Scotland, 2nd Floor, Hanover Buildings, 66 Rose Street, Edinburgh EH2 2NN *Correspondence to: Professor Crispian Scully CBE Email: [email protected]

Refereed Paper © British Dental Journal 2005; 199: 339–343 Fig. 1 Squamous cell carcinoma Fig. 2 Lichen planus

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sexually transmitted. There are many immunolog- ERYTHEMA MULTIFORME ical findings in BS similar to those seen in recur- Erythema multiforme (EM) is an uncommon rent aphthous stomatitis, with T suppressor cell acute often recurrent reaction affecting mucocu- dysfunction and increased polymorphonuclear taneous tissues, seen especially in younger males. leucocyte motility (Article 1). There is a genetic The aetiology of erythema multiforme (EM) is predisposition. Many of the features of BS (erythe- unclear in most patients, but it appears to be an ma nodosum, arthralgia, uveitis) are common to immunological hypersensitivity reaction, leading established immune complex diseases. to sub- and intra-epithelial vesiculation. There may be a genetic predisposition with associations Clinical features of recurrent EM with various HLA haplotypes. Behcet’s syndrome is a chronic, sometimes life- EM is triggered by a range of usually exoge- threatening disorder characterised mainly by: nous factors, such as: • Recurrent aphthous stomatitis (RAS) in 90–100% • Infective agents , particularly HSV (herpes- • Recurrent painful genital ulcers that tend to associated EM: HAEM) and the bacterium heal with scars Mycoplasma pneumoniae • Ocular lesions: iridocyclitis, uveitis, retinal • Drugs such as sulfonamides (e.g. co-trimoxa- vascular changes, and optic atrophy may occur zole), cephalosporins, aminopenicillins, and • CNS lesions many others • Skin lesions: erythema nodosum, papulopus- • Food additives or chemicals. tular lesions and acneiform nodules. Clinical features The joints, epididymis, heart, intestinal tract, EM ranges from limited disease (Minor EM) to vascular system and most other systems may severe, widespread life-threatening illness (Major also be involved. EM). Most patients (70%) in either form, have oral However, very non-specific signs and symp- lesions, which may precede lesions on other strat- toms, which may be recurrent, may precede the ified squamous epithelia (eyes, genitals or skin), onset of the mucosal membrane ulcerations by or may arise in isolation. Oral EM typically pres- six months to five years. ents with macules which evolve to blisters and ulcers. The lips become swollen, cracked, bleeding Differential diagnosis and crusted. This is from a range of other syndromes that can Minor EM affects only one site and may affect affect the eyes, mouth and skin — such as vari- mouth alone, or skin or other mucosae. Rashes are ous dermatological disorders and infections. various but typically ‘iris’ or ‘target’ lesions or bullae on extremities. Diagnosis Major EM (Stevens-Johnson syndrome; SJS) BS can be very difficult to diagnose, but the almost invariably involves the oral mucosa and International Study Group for Behcet’s Disease causes widespread lesions affecting mouth, eyes, (ISGBD) criteria suggest the diagnosis be made pharynx, larynx, oesophagus, skin and genitals. on clinical grounds alone on the basis of RAS plus two or more of the following: Diagnosis • Recurrent genital ulceration There are no specific diagnostic tests for EM. • Eye lesions Therefore, the diagnosis is mainly clinical, and it • Skin lesions can be difficult to differentiate between it and • Pathergy — a >2 mm diameter erythematous viral stomatitis, pemphigus, toxic epidermal nodule or pustule forming 24–48 hours after necrolysis, and sub-epithelial immune blistering sterile subcutaneous puncture of the forearm. disorders. Serology for HSV or Mycoplasma pneumoniae, or other micro-organisms, and biop- Investigations sy of perilesional tissue, with histological and There is no specific diagnostic test, but typing for immunostaining examination, are essential if a specific human leukocyte antigens (HLA B5101) specific diagnosis is required. can help. Disease activity may be assessed by serum levels of various proteins, such as the Management acute phase proteins (erythrocyte sedimentation Spontaneous healing can be slow — up to two to rate (ESR) and C-reactive protein (CRP) or anti- three weeks in minor EM and up to six weeks in bodies to intermediate filaments. major EM. Treatment is thus indicated but controversial Management and thus specialist care should be sought. Sup- In the face of the difficult diagnosis and serious portive care is important; a liquid diet and even potential complications, patients with suspected intravenous fluid therapy may be necessary. Oral BS should be referred early for specialist advice. hygiene should be improved with 0.2% aqueous chlorhexidine mouthbaths. Websites and patient information The use of corticosteroids is controversial but http://www.aarda.org/indexf.html minor EM may respond to topical corticosteroids. Patients with major EM such as the Stevens- LICHEN PLANUS Johnson syndrome may need to be admitted for Lichen planus is discussed in Article 5. hospital care. Major EM patients should be

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referred for treatment with systemic corticos- ant cytokine and leukocyte enzyme release and teroids or other immunomodulatory drugs. detachment of the basal cells from the BMZ.

Websites and patient information Clinical features http://www.emedicine.com/EMERG/topic173.htm The oral lesions (Figs 3–5) affect especially the gin- givae and palate, and include bullae or vesicles PEMPHIGOID which are tense, may be blood-filled and remain Pemphigoid is the term given to a group of intact for several days. Persistent irregular erosions uncommon sub-epithelial immunologically- or ulcers appear after the blisters burst and, if on mediated vesiculobullous disorders (SEIMD) the gingivae, can produce desquamative gingivitis which can affect stratified squamous epithelium, — the most common oral finding. This is charac- characterised by damage to one of the protein terised by erythematous, ulcerated, tender gingivae constituents of the basement membrane zone in a patchy, rather than continuous distribution. (BMZ) anchoring filaments components. A num- The majority of people with MMP have only ber of other sub-epithelial vesicullobullous disor- oral lesions, but genital involvement can cause ders may produce similar clinical features (Table 1). great morbidity and untreated ocular involve- ment can lead to blindness. Nasal, laryngeal and Table 1 Uncommon sub-epithelial vesiculobullous skin blisters are rare. disorders Pemphigoid variants Acquired epidermolysis bullosa (EBA) Toxic epidermal necrolysis (TEN) Erythema multiforme Dermatitis herpetiformis Linear IgA disease Chronic bullous dermatosis of childhood

The main types of pemphigoid that involve the mouth are: • Mucous membrane pemphigoid (MMP), in Fig. 3 Pemphigoid which mucosal lesions predominate but skin lesions are rare • Oral mucosal pemphigoid — patients with oral lesions only, without a progressive ocular scarring process and without serologic reac- tivity to bullous pemphigoid (BP) antigens • Bullous pemphigoid (BP) — which affects mainly the skin • Ocular pemphigoid — which is sometimes termed cicatricial pemphigoid (CP) since it Fig. 4 Mucous membrane may cause serious conjunctival scarring. pemphigoid

However, most of the literature has failed to dis- tinguish these variants, since their distinction has only recently been recognised, and therefore the following discussion groups them together.

MUCOUS MEMBRANE/ORAL PEMPHIGOID Mucous membrane pemphigoid (benign mucous membrane pemphigoid) is an uncommon chronic disease, twice as common in females, and usually Fig. 5 Pemphigoid: desquamative presenting in the fifth to sixth decades. gingivitis Mucous membrane pemphigoid is an autoim- mune type of disorder with a genetic predisposi- tion. The precipitating event is unclear in most Diagnosis cases, but rare cases are drug-induced (eg by The oral lesions of pemphigoid may be confused furosemide or penicillamine). It is characterised clinically with pemphigus, or occasionally erosive immunologically by deposition of IgG and C3 lichen planus, erythema multiforme or the sub- antibodies directed against the epithelial base- epithelial blistering conditions shown in Table 1. ment membrane zone (BMZ). There are also circu- Biopsy of perilesional tissue, with histologi- lating autoantibodies to BMZ components pres- cal and immunostaining examination can there- ent in hemi-desmosomes or the lamina lucida. fore be essential to the diagnosis. The antibodies damage the BMZ and histologically there is a sub-basilar split. The Management pathogenesis probably includes complement- Spontaneous remission is rare, and thus treatment mediated sequestration of leukocytes with result- is indicated. Specialist advice is usually needed.

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Systemic manifestations must be given atten- examination are important, but biopsy of peri- tion. For this reason, an ophthalmology consul- lesional tissue, with histological and immunos- tation can be needed. taining examination are crucial. Serum should The majority of cases respond well to topical be collected for antibody titres. corticosteroids. Non-steroidal immunosuppres- sive agents such as tacrolimus may be needed if Management the response is inadequate. Before the introduction of corticosteroids, pemphi- Severe pemphigoid may need to be treated gus vulgaris typically was fatal, mainly from dehy- with immunosuppression using systemic aza- dration or secondary systemic infections. Current thioprine or corticosteroids. treatment, by systemic immunosuppression, usual- ly with steroids, or azathioprine or mycophenolate Website and patient information mofetil, has significantly reduced the mortality to http://www.dent.ucla.edu/pic/members/MMP/in about 10%. Specialist care is mandatory. dex.html Websites and patient information PEMPHIGUS http://www.pemphigus.org Pemphigus is a group of fortunately rare, potential- ly life-threatening chronic diseases characterised Blood disorders that can cause ulcers include by epithelial blistering affecting cutaneous and/or mainly the leukaemias, associated with cytotoxic mucosal surfaces. There are several variants with therapy, viral, bacterial or fungal infection, or different autoantibody profiles and clinical mani- non-specific. Other oral features of leukaemia festations (Table 2) but the main type is pemphigus may include purpura, gingival bleeding, recurrent vulgaris; this includes an uncommon variant pem- herpes labialis, and candidosis. phigus vegetans. Pemphigus vulgaris is seen main- Gastrointestinal disease may produce soreness or ly in middle aged and elderly females of Mediter- mouth ulcers. A few patients with aphthae have ranean, Ashkenazi Jewish or South Asian descent. intestinal disease such as coeliac disease causing Pemphigus vulgaris is an autoimmune disor- malabsorption and deficiencies of haematinics, der in which there is fairly strong genetic back- when they may also develop angular stomatitis or ground. Rare cases have been triggered by med- glossitis. Crohn’s disease and pyostomatitis vege- ications (especially captopril, penicillamine, tans may also cause ulcers. Orofacial granulo- rifampicin and diclofenac) or other factors. matosis (OFG), which has many features reminis- cent of Crohn’s disease, may also cause Table 2. Main types of pemphigus involving the mouth ulceration. Miscellaneous uncommon diseases such as Variant Oral Main Localisation Antibodies lesions antigens of antogens lupus erythematosus can cause ulcers.

Pemphigus Common Dsg 3 Desmosomes IgG DIFFERENTIAL DIAGNOSIS OF ORAL vulgaris localised to ULCERATION mucosae The most important feature of ulceration is (Mucosal) whether the ulcer is single, multiple or persistent. Multiple non-persistent ulcers are most common- Pemphigus Common Dsg 3 Desmosomes IgG vulgaris also Dsg 1 ly caused by viral infections or aphthae, when the involving skin/ ulcers heal spontaneously, usually within a week other mucosae to a month. If this is not the case, or if the ulcers (Muco-cutaneous) clinically do not appear to be aphthae, an alterna- tive diagnosis should be considered. The autoantibodies are directed against strati- A single ulcer that persists may be caused by neo- fied squamous epithelial desmosomes, particular- plasia such as carcinoma or by chronic trauma, a ly the proteins desmoglein-3 (Dsg3) and plako- chronic skin disease such as pemphigus, or a globin (Table 2). Damage to the desmosomes leads chronic infection such as syphilis, tuberculosis or to loss of cell-cell contact (acantholysis), and thus mycosis. intra-epithelial vesiculation. Multiple persistent ulcers are mainly caused by skin diseases such as lichen planus, pemphigoid Clinical features or pemphigus, gastrointestinal disease, blood dis- Pemphigus vulgaris typically runs a chronic ease, immune defect or drugs. course, causing blisters, erosions and ulcers on In cases where the diagnosis is unclear, or the mucosae and blisters and scabs on the skin. where there is a single persistent ulcer, specialist Oral lesions are common, may be an early mani- referral is usually indicated. festation and mimic those of pemphigoid in par- ticular. Blisters rapidly break down to leave ero- DIAGNOSIS OF ORAL ULCERATION sions seen mainly on the palate, buccal mucosa, Making a diagnosis of the cause for oral ulcer- lips and gingiva. ation is based mainly on the history and clini- cal features. The number, persistence, shape, Diagnosis character of the edge of the ulcer and the To differentiate pemphigus from other vesicu- appearance of the ulcer base should also be lobullous diseases, a careful history and physical noted. Ulcers should always be examined for

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induration (firmness on palpation), which may down the aspirator). Place the biopsy specimen be indicative of malignancy. The cervical on to a small piece of paper before immersing in lymph nodes must be examined. fixative, to prevent curling. Unless the cause is undoubtedly local, general Put the specimen into a labelled pot, ideally physical examination is also indicated, looking in at least 10 times its own volume of buffered especially for mucocutaneous lesions, other formalin, and leave at room temperature. lymphadenopathy or fever, since it is crucial to Suture the wound if necessary, using detect systemic causes such as leukaemia or HIV resorbable sutures (eg Vicryl). infection (Fig. 6). MANAGEMENT OF ORAL ULCERATION • Treat the underlying cause • Remove aetiological factors • Prescribe a chlorhexidine 0.2% mouthwash • Maintain good oral hygiene • A benzydamine mouthwash or spray or other topical agents (Table 3) may help ease discomfort.

Table 3 Topical agents which may reduce pain from mucosal lesions Agent Use Comments

Fig. 6 HIV-associated ulceration Benzydamine hydrochloride Rinse or spray every 1.5 to 3 hours Effective in reducing discomfort Lidocaine Topical 4% solution may ease pain Also reduces taste sensitivity Biopsy Carboxymethylcellulose Paste or powder used after meals Available containing triamcinolone Informed consent is mandatory for biopsy, par- to protect area ticularly noting the likelihood of post-operative discomfort, and the possibility of bleeding or REFERRAL OF PATIENTS WITH ORAL ULCERATION bruising or sensory loss. Care must be taken not Patients with single ulcers persisting more than to produce undue anxiety; some patients equate three weeks, indurated ulcers, or multiple persist- biopsy with a diagnosis of cancer. Perhaps the ent ulcers may benefit from a specialist opinion. most difficult and important consideration is Patients with recalcitrant ulcers, or a systemic which part of the lesion should be included in the background to mouth ulcers, or needing investi- biopsy specimen. gation, may also benefit from a specialist referral. As a general rule, the biopsy should include Features that might suggest a systemic back- lesional and normal tissue. In the case of ground to mouth ulcers include: ulcerated mucosal lesions, most histopathological • Extraoral features such as skin, ocular, or gen- information is gleaned from the peri-lesional tis- ital lesions (suggestive of Behcet’s syndrome); sue since by definition most epithelium is lost purpura, fever, lymphadenopathy, from the ulcer itself. The same usually applies for hepatomegaly, or splenomegaly (which may skin diseases affecting the mouth, where the be found in leukaemia), chronic cough (sug- epithelium in the area mainly affected will, more gestive of TB or a mycosis), gastrointestinal often than not, separate before it ends up under complaints (eg pain, altered bowel habits, the microscope, and results will be compromised. blood in faeces), weakness, loss of weight or, in In the case of a suspected potentially malignant or children, a failure to thrive. malignant lesion, any red area should ideally be • An atypical history or ulcer behaviour such as included in the specimen. In some cases where no onset of ulcers in later adult life, exacerbation obvious site can be chosen, vital staining with of ulcers, severe aphthae, or aphthae unre- ‘toluidine blue’ may first be indicated. sponsive to topical steroids. A biopsy punch has the advantage that the • Other oral lesions, especially infections sugges- incision is controlled, an adequate specimen is tive of HIV/AIDS (candidosis, herpetic lesions, obtained (typically 4 mm or 6 mm diameter) and necrotising gingivitis or periodontitis, hairy suturing may not be required. However, in the leukoplakia or Kaposi’s sarcoma), glossitis or skin disorders, the punch can sometimes split the angular cheilitis (suggestive of a haematinic epithelium or detach it from the lamina propria. state), or petechiae or gingival bleeding or When a scalpel is used, a specimen of elliptical swelling (raising the possibility of leukaemia). shape is usually taken, most commonly from an edge of the lesion. Investigations sometimes indicated include: • blood tests to exclude haematinic deficiencies, Patients to refer Procedure leukaemia or HIV infection Malignancy A local analgesic should be given, although in a few • microbiological and serological investigations HIV related ulceration cases, conscious sedation may also be necessary. to exclude infection Syphilis Make the incisions using a scalpel with a • biopsy TB number 15 blade. Do not squeeze the specimen • immunological studies to exclude skin diseases Drug related ulceration with forceps while trying to dissect the deep and HIV Systemic disease margin. A suture is best used for this purpose • imaging to exclude TB, deep mycoses, Mucocutaneous disorders (and also to protect the specimen from going carcinoma, or sarcoidosis.

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