doi: 10.1111/j.1600-0714.2008.00722.

J Oral Pathol Med (2009) 38: 241253 2008 John Wiley & Sons A/S All rights reserved interscience.wiley.com/journal/jop

REVIEW ARTICLE

Long-standing oral ulcers: proposal for a new S-C-D classication system

D. Compilato1, N. Cirillo2, N. Termine1, A. R. Kerr3, C. Paderni1, D. Ciavarella4, G. Campisi1
1 Department of Oral Sciences, University of Palermo, Palermo, Italy; 2Regional Center on Craniofacial Malformations-MRI, 1st School of Medicine and Surgery, II University of Naples, Naples, Italy; 3Department of Oral and Maxillofacial Pathology Radiology and Medicine, New York University College of Dentistry, New York, NY, USA; 4Department of Surgical Sciences, Faculty of Medicine, School of Dentistry, University of Foggia, Foggia, Italy

Persistent oral ulcers and erosions can be the nal common manifestation, sometimes clinically indistinguishable, of a diverse spectrum of conditions ranging from traumatic lesions, infectious diseases, systemic and local immune-mediated lesions up to neoplasms. The process of making correct diagnosis for persistent oral ulcers still represents a challenge to clinicians. Major diagnostic criteria should include the clinical appearance of both ulcer and surrounding non-ulcerated mucosa, together with the evaluation of associated signs and symptoms, such as: number (single or multiple), shape, severity of the ulcer(s), conditions of remaining mucosa (white, red or with vesiculo-bullous lesions) and systemic involvement (e.g. fever, lymphadenopathy or evaluation of haematological changes). The aim of this paper was to review the literature relating to persistent oral ulcers and provide a helpful, clinical-based diagnostic tool for recognising long-standing ulcers in clinical dental practice. The authors, therefore, suggest distinguishing SIMPLE, COMPLEX AND DESTROYING (S-C-D system) ulcerations, as each requires different diagnostic evaluations and management. This classication has arisen from studying the current English literature relating to this topic, performed using MEDLINE / PubMed / Ovid databases (key words: oral ulcerations, persistent oral ulcers, systemic diseases and oral ulcers, drugs and oral ulcers). J Oral Pathol Med (2009) 38: 241253 Keywords: lichen planus; oral carcinoma; oral ulcers; traumatic ulcer; vesiculo-bullous diseases

Introduction
Oral erosions are characterized as the partial loss of epithelial thickness; in contrast, an oral ulcer or ulceration is characterized by the complete loss of epithelium accompanied by a variable loss of the underlying connective tissue, resulting in a crateriform appearance, which may be augmented by oedema andor a proliferation of the surrounding tissue (1). Ulcers and erosions are the nal common manifestation of a spectrum of conditions ranging from autoimmune diseases to neoplastic, traumatic, infectious lesions, nutritional deciencies and drug reactions (24), and they represent a diagnostic challenge for dental practitioners. Diagnosis is contingent upon a carefully elicited history and detailed physical examination. The most important feature of an ulcer is its chronic outcome, because a persistent ulcer can be a sign of squamous cell carcinoma, particularly when associated with any induration (3). Other distinguishing features are the number, shape, size and border features (2, 5). Coleman has published various important features which can facilitate the diagnosis of ulcers (6): 1 Onset of the lesions as acute or gradual 2 Duration of the lesions as limited (24 weeks) or protracted (more than 4 weeks) 3 Recurrence or progression of the lesions 4 Presence of vesicles, white or red lesions preceding the ulcers 5 Presence of skin, eye or genital lesions 6 Concurrence of systemic manifestations 7 Medication taken by the patient Unless the cause of ulceration is evidently local, a general physical examination andor laboratory evaluations may be warranted to diagnose ulcers which are secondary to systemic diseases. A biopsy may also be indicated, especially when neoplasm remains in the dierential diagnosis. The clinical course and suspected cause of ulcerative lesions can be combined to form a

Correspondence: Professor Giuseppina Campisi, Department of Oral Sciences, University of Palermo, Via del Vespro 129, 90127 PALERMO, Italy. Tel/Fax: +39 091 655 2236, E-mail: campisi@odonto.unipa.it Accepted for publication September 13, 2008

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dierential diagnostic classication, as suggested by Coleman and Nelson (1993) (6): 1 Oral ulcerations with acute onset and short duration, that include bacterial infections or injury and generalized viral infections; 2 Oral ulcerations with chronic or a recurrent course: genetic diseases, recurrent viral and idiopathic diseases, autoimmune diseases, granulomatous diseases and malignancy. There is, however, much overlap in this classication system; examples include: (i) a traumatic ulcer which becomes chronic if the causal factor is not removed; (ii) bacterial and viral infections which demonstrate a chronic course in immuno-compromised patients; (iii) recurrent oral ulcerations, such as minor aphthous ulcers, that are included in the same group of chronic ulcers whilst proving to be acute ulcers with a duration <23 weeks (7, 8). A simpler and more intuitive classication of oral ulcerations, based upon evident clinical features, would, therefore, be of great use to the general dental practitioner. This is particularly relevant for chronic ulcers, which may be caused by serious diseases such as cancer. In this regard, it is disappointing that only a minority of dentists are capable of recognizing the most common form andor early lesions, which are predictive of oral squamous cell carcinoma (OSCC) (9). The dearth of dental practitioners who are capable of identifying the basic clinical aspects of chronic ulcers may eventually lead to a misdiagnosis of other potentially fatal diseases, such as pemphigus and hematological neoplasms. Bearing this in mind, the authors of this paper attempt to develop a new system, named S-C-D, for facilitating the diagnostic algorithm of persistent oral ulcerations.

Table 1 Classication of persistent oral ulcerations Simple ulceration Traumatic ulcers Associated with mechanical trauma Necrotizing sialometaplasia Eosinophilic ulcer Riga-Fede disease Familial dysautonomia Malignancies Oral squamous cell carcinoma Malignant salivary gland tumors (i.e. mucoepidermoid carcinoma, adenoid cystic carcinoma) Kaposis sarcoma Hematological neoplasms Melanoma Metastases Syphilis Infectious granulomatous diseases Tuberculosis Actinomycosis Deep mycosis (as rst manifestation) Oral lichen planus Lichenoid mucositis lichenoid drug reaction Graft-vs.-Host disease Lupus erythemathosus Oral squamous cell carcinoma Atrophicerosive lichen planus Nutritional deciencies Hematological disorders Neutropenia Cyclic neutropenia Agranulocytosis Leukemias (frequent) Hodgkins lymphoma (rare) Non Hodgkins lymphoma Multiple myeloma (rare) Histiocytosis X Chemotherapy and radiotherapy associated oral mucositis Drug-induced oral lesions Oral squamous cell carcinoma Bullous oral lichen planus Pemphigus Immune-mediated sub-epithelial blistering diseases Syphilis Infectious granulomatous diseases Tuberculosis Actinomycosis Non infectious granulomatous disease Sarcoidosis Wegeners granulomatosis Oral squamous cell carcinoma Noma Deep mycosis

Complex ulceration Associated with white lesions

Associated with red lesions

Persistent oral ulcerations a classication

Ulcers that do not heal within 2 weeks may be considered as persistent or chronic (10). In this paper, we propose a new diagnostic approach, namely the S-C-D system (see Table 1 for details), which is based upon the evident clinical presentation of the lesion(s). It may, therefore, be of use to general dental practitioners and oral medicine specialists. The dening criteria are: the number of lesions, the appearance of the surrounding mucosa, and the presence of extra-oral manifestations, as follows: 1 a single ulcer, without the involvement of remaining mucosa: a simple (S) ulceration 2 single or multiple ulcers, with changes to the surrounding mucosa, skin and or systemic manifestations: complex (C) ulceration. In this case, clinicians should evaluate the characteristics of associated lesion(s), as follows: a. white b. red c. vesiculo-bullous 3 Diffuse lesions with tissue destruction, severe systemic involvement: destroying (D) ulceration
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Associated with vesiculo-bullous lesions Destroying ulceration Slightly raising

Rapidly progressing

Simple ulceration An important feature to establish is whether one or more than one ulcer is present and whether the remaining mucosa is healthy, because a spectrum of conditions usually manifest themselves as single lesions (Table 1). When a patient presents a single and isolated oral ulcer in a given site, a dierential diagnosis should always include: chronic trauma, neoplasms (such as OSCC), haematological neoplasms and salivary gland malignancies (mucoepidermoid and adenoid cystic car-

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cinoma) (3), although unusual causes, such as tuberculosis, necrotizing sialometaplasia and syphilis could also be considered (1113). Solitary ulcers persisting for more than 2 weeks after treatment without signs of evident healing must be taken seriously and a biopsy is mandatory.
Traumatic ulcer

Traumatic ulcers resulting from a physical injury are probably the most common form of oral ulceration. Chronic ulcers associated with mechanical trauma are often found on the buccal mucosa, the labial mucosa of the upper and lower lips, and the lateral border of the tongue (Fig. 1a), all sites that may be injured by dentition. Lesions of the gingiva and mucobuccal fold may occur from other sources of irritation, such as tooth-brushing, which can create linear erosions along the free gingival margins, eventually associated with areas of hyperkeratosis.

Chronic traumatic ulcer is usually solitary, covered by a white or yellow-tan brin clot, and located in an area subject to injury. An ulcer caused by recurring trauma may be painful and exhibit an elevated, rolled border which is rm when palpated. The increased consistency is due to the formation of scar tissue and chronic inammatory inltrate. Traumatic ulceration on the lingual frenum or, more commonly, on the ventral surface of the tongue in new-borns and infants, in association with natal or neonatal teeth, identies a rare condition called Riga-Fede disease (14). Occasionally, oral ulcerative lesions, labelled as factitial ulcers, result from self-mutilating conditions (15) (Fig. 1b), which may be concurrent with a series of psychiatric disorders, developmental deciencies or syndromes (16), such as hereditary sensory and autonomic neuropathy, a rare syndrome characterized by congenital insensitivity to pain that often results in severe oral mutilations (17).

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Figure 1 (A) Chronic traumatic ulcer on the lateral surface of the tongue. (B) Factitial ulcer of the tongue in an autistic child. (C) Necrotizing sialometaplasia of the hard palate. (D) Clinical aspect of oral carcinoma appearing as a non-bleeding chronic tongue ulcer.
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Finally, two characteristic ulcerative lesions of the oral mucosa which recognize a plausible traumatic aetiology are eosinophilic ulcers (i.e. traumatic granuloma, traumatic ulcerative granuloma with stroma eosinophilia, eosinophilic granuloma of the tongue) and necrotizing sialometaplasia. Traumatic granuloma is a chronic, benign, self-limiting oral lesion, manifesting itself most commonly as a solitary ulceration, with elevated and indurated borders (18) of the lateral or ventral surface of the tongue (60% of lesions) (18), but it can aect any region of the oral mucosa. Its histological peculiarity is the presence of mitotically-active, large mononuclear cells with a round-to-ovoid pale nucleus, and this feature has occasionally led to the erroneous diagnosis of a lymphohistiocytic malignant condition (19). Necrotizing sialometaplasia is a locally destructive inammatory condition of the salivary glands. It is an uncommon disorder that presents a traumatic basis and can be a feature of bulimia nervosa (20). The hard palate is aected more often than the soft palate and two-thirds of palatal cases are unilateral (8) (Fig. 1c). The condition initially appears as a non-ulcerated swelling, often associated with pain or paresthesia. Within 23 weeks, necrotic tissue sloughs out, leaving a crateriform and deep ulcer with a lobular and yellowgrey bottom that can range from <1 to >5 cm in diameter (8); lesions spontaneously heal in a few weeks. Its clinical features may mimic those of OSCC and, histologically, ductal squamous metaplasia may be erroneously interpreted as a SCC. If metaplasia is demonstrated in salivary gland ducts, the ulcer may be mistaken for mucoepidermoid carcinoma. However, necrosis and the maintenance of lobular architecture distinguish this lesion from a neoplasm.
Malignancies

Oral malignancies manifesting themselves as a simple ulceration include: OSCC (21); salivary gland malignancies (less frequently), such as mucoepi dermoid carcinoma (22) and adenoid cystic carcinoma (23); oral melanoma; Kaposis sarcoma; and haematological neoplasms, such as lymphoproliferative and myeloproliferative diseases (usually multiple myeloma) (8). Furthermore, the oral cavity is a rare but occasional target for metastases, mainly arising from mainly lung, breast, kidney, gastric (24) and colon tumours. Oral squamous cell carcinoma. Oral squamous cell carcinoma arises from mucosal surface epithelium and represents over 90% of oral and pharyngeal cancers. It presents with a variety of clinical aspects that are in relation to the growing modalities of the tumour; indeed, lesions can present as exophytic, with a papillary or verruciform aspect, or as endophytic with the aspect of a penetrating ulcer. In the earliest stages, carcinomas usually appear as painless, red, speckled or with patches, and only a minority are ulcerated. As the carcinoma enlarges it may develop into a raised nodule or it may become ulcerated. The neoplastic ulcer appears rm and it adheres to underlying tissues on palpation, with a base
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covered by brin and a rounded, markedly indurated border (Fig. 1d). These ulcers are typically painless unless local tissue destruction is deep (25). Ulceration may cause soreness or a stinging pain when sharplyavoured food is eaten. Bleeding of the ulcers, either spontaneously or from mild trauma, is a late feature. When aecting the tongue, deep ulcers may give rise to lingual andor hypoglossal nerve damage with or without dysarthria or dysphagia (26). Malignant salivary gland neoplasms. Although most salivary gland tumours initially manifest themselves as a swelling, ulceration could represent a very common event in the clinical evolution of the lesion. The most common salivary gland tumours that can present as oral ulceration are mucoepidermoid carcinoma and adenoid cystic carcinoma. Mucoepidermoid carcinoma is the most common malignant tumour of the salivary glands, occurring principally between the third and sixth decade of life (27, 28). Furthermore, it is the most common malignant salivary gland tumour to occur in children and adolescents of <20 years of age. When it arises in minor salivary glands, it can be located on the palate, retromolar area, oor of the mouth, buccal mucosa, lips and tongue and it has a slight predilection for women (28, 29). Clinical manifestations of mucoepidermoid carcinoma are strictly associated with the grade of malignancy. Low-grade tumours present a long period of asymptomatic growth. In the oral cavity the tumour often resembles a mucocele and it occasionally uctuates in the presence of a cystic component; it can, however, evolve into an ulcer. High-grade tumours often grow quickly and induce pain and ulceration of the oral mucosa, particularly when they arise in the minor salivary gland of the palate. Adenoid cystic carcinoma can occur in any salivary gland site, but approximately 50% develop within the minor salivary glands. The palate is the most common site for minor salivary gland tumours where it represents 815% of all malignant tumours, followed by the parotid and submandibular glands. The greatest incidence occurs between the age of 2060 years with a predilection for the female. A palatal tumour often presents as an ulcerated area that mimics the necrotizing sialometaplasia. Complex ulceration Oral ulcers may be associated with other clinically evident lesions aecting the oral mucosa or a feature of various systemic disorders, such as skin, haematological and gastrointestinal diseases (8). The following section is limited to a review of persistent oral ulcers, which are associated with white, red and vesiculo-bullous lesions.
Persistent oral ulcers association with white lesions

Oral lichen planus (OLP), lichenoid lesions (LL), discoid or systemic lupus erythematosus (DLE or SLE) may be associated with ulcerations andor erosions (8). OSCC can also present as a persistent ulcer associated to white areas. OLP and lichenoid lesions. Oral lichen planus is a chronic inammatory disorder aecting stratied squa-

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mous epithelia with an autoimmune pathogenesis in which a key role is played by auto-cytotoxic CD8+ T cells that trigger apoptosis of the basal cells of oral epithelium (30, 31). Histologically, it is characterized by a dense band-like subepithelial T-lymphocytic inltrate, increased numbers of intra-epithelial lymphocytes, basal cell degeneration with the formation of colloid or Civatte bodies (32). OLP may manifest itself in various clinical forms, including: reticular, plaque, atrophic (erythematous) and erosive (ulcerated, bullous) (33) (Fig. 2a), all of which are occasionally concomitant. An important clinical feature of OLP is its tendency to occur with multiple and bilateral lesions. Erythematous or atrophic OLP generally occurs on the dorsum of the tongue, causing atrophy of the

liform papillae accompanied by reticular lesions (34,35); painful is presents, especially after the consumption of spicy and acid foods. Erythematous lesions aecting the gingiva result in desquamative gingivitis, the most common type of gingival LP (3639). This feature is not pathognomonic for OLP as other vesiculoerosive diseases (40) (see vesiculo-bullous diseases) also produce desquamative gingivitis, and desquamative gingivitis is not easily identied as LP unless there are coexistent reticular lesions on the gingiva or elsewhere in the oral cavity. Lichenoid lesions, principally lichenoid reactions (LR) to medication, may be mucocutaneous in distribution and clinicallyhistologically resemble LP (33). Several drugs (4147) have been implicated in

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Figure 2 (A) Bullous oral lichen planus. (B) Non-Hodgkins lymphoma, manifesting as an oral ulcer. (C) Multiple ulcers on the gingival mucosa in a neutropenic patient. (D) Oral mucositis after chemoradiotherapy for oral carcinoma.
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LR. Oral drug-induced LRs tend to manifest themselves as unilateral (48) and erosive (41) lesions, similar to erosive OLP, and they are often localized on the buccal mucosa. Furthermore, LLs can be observed on the oral mucosa near dental materials, such as amalgams (49), composite resins (50), cobalt (51) and gold (52). The histology is not specic and it may occasionally be characterized by a more diuse lymphocytic inltrate, with eosinophils and plasma cells, and there may be more colloid bodies than in classic LP (33, 34). The most reliable means of Codice campo modicato diagnosing LRs is if the reaction remits with the withdrawal andor the replacement of drug or dental materials, which are considered as causal agents (33). A particular form of lichenoid lesions are oral manifestations of chronic graft-vs.-host disease (cGVHD). cGVHD is a multisystemic syndrome and it represents the most common complication of allogeneic bone marrow or peripheral stem cell transplantation, resulting from an adverse reaction of the donors immune cells against the hosts tissues (53). The basis of cGVHD is the recognition of foreign transplantation antigens by transplantated lymphocytes, expressed by the cells of the immunosuppressed host with subsequent immune-mediated damage to host tissues. Skin, liver, airways, intestinal tract and mucous membranes are the most frequent organs to be involved in cGVHD. Persistent oral involvement is typically present in the chronic form and it is characterized by the presence of a gradual onset of xerostomia and lichenoid changes, clinically similar to LP with associated erosiveulcerative lesions in more severe cases (54, 55). Lupus erythematosus. Lupus erythematosus (LE) is a chronic inammatory connective tissue disease, linked to the production of multiple autoantibodies, principally antinuclear antibodies (anti-DNA and anti-RNA). It has four main clinico-pathological forms: SLE, chronic cutaneous LE (CCLE), acute cutaneous LE and subacute cutaneous LE (56). SLE is a common multisystem connective tissue disease of unknown cause, aecting the skin, joints, kidneys, lungs, nervous system, serous membranes and other systems. The most common form of CCLE is DLE (56), a skin disease with mucocutaneous lesions, which are indistinguishable from those of SLE. In most cases, the oral manifestations of SLE and DLE essentially appear clinically identical to erosive OLP lesions. Unlike LP oral lesions, however, LE oral lesions rarely occur in the absence of skin lesions (57, 58). An ulcerated or atrophic, erythematous central zone, surrounded by white, ne, radiating striae, characterizes the LE oral lesion. Occasionally the erythematous atrophic central region of a lesion may reveal a ne stippling of white dots. As with erosive OLP, ulcerative and atrophic LE oral lesions may be painful, especially when exposed to acidic or salty foods. Complications of these oral lesions include painful ulceration and a malignant transformation to SCC (59).

Persistent oral ulcers association with red lesions

When single or multiple ulcers are associated with red lesions, nutritional deciencies, together with haematological and endocrinological abnormalities, should be evaluated. Chronic atrophicerosive mucosal lesions are known to be due to nutritional deciencies, in addition to vitamin B12, folic acid, or iron deciencies. A number of haematological disorders characterized by neutropenia andor impaired neutrophil activity may give rise to mucosal ulcers of the mouth, described as oral neutropenic ulcerations (6064). At least partially, diabetic oral ulcers may also arise as a consequence of neutrophil dysfunctions. Furthermore, leukemias (65, 66), lymphomas (67, 68), histiocytosis X (69, 70) and plasmocytoma should be considered as conditions which are potentially responsible for oral ulcers. Adverse reactions to dental materials (71) or drugs (47, 7276), in addition to the use of chemotherapeutical agents may also cause persistent ulcerations in a context of erythema and mucositis (7780). Finally, OSCC can manifest itself as an ulcerated area associated with red lesions. In the following section, we will analyze in a concise but detailed way the most important haematological diseases associated to oral ulceration and oral mucositis, which are associated with chemotherapy and head and neck radiation used for the treatment of cancer. Haematological diseases. The most important haematological diseases which could manifest themselves with oral ulcers are: neutropenia, cyclic neutropenia, agranulocytosis, and neoplasms, particularly leukaemia and non-Hodgkins lymphoma (Fig. 2b). A detailed review of non-Hodgkins lymphoma of the mouth can be reviewed elsewhere (81). Although a presumptive diagnosis may be formulated by evaluating clinical aspects and blood analyses, these serious diseases must be monitored by haematologists. Neutropenia refers to a decrease in the number of circulating neutrophils below 1500 per mm3 in an adult. In cyclic neuropenia, regular periodic reductions in the neutrophil population of the aected patient occur; agranulocytosis is a condition in which the cells of the granulocytic series, particularly neutrophils, are absent. These conditions are often associated with an increased susceptibility of the patient to bacterial infections rather than a viral or fungal infection, particularly if the other cells in the immune system are still intact. Oral lesions are often the initial sign of a decrease in neutrophils and they are characterized by extreme gingival redness, possibly aggressive periodontitis and ulcerations (Fig. 2c). This is principally due to opportunistic infections that usually involve the gingival mucosa, probably due to a heavy bacterial colonization of this area (82). Neutropenic ulcerations are usually multiple, covered by a yellow pseudo-membrane, and the surrounding mucosa may be erythematous. Patients suering from leukemia may also present with a neutropenic ulceration of the oral mucosa, comprising of typically deep, punched-out lesions with a grayishwhite necrotic base (65). Occasionally, the leukemic cells inltrate the soft oral tissue, particular gingival tissues, to

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produce a diuse, boggy, non-tender swelling that may or may not be ulcerated (66). Oral mucositis. Mucositis is associated with chemotherapy, and head and neck radiation used for the treatment of cancer, but also in the conditioning prior to bone marrow transplantation (78, 79, 83). It is characterized by erythema and ulceration in the orooesophageal and gastrointestinal mucosa that results in pain, dysphagia, diarrhoea and dysfunction, depending on the tissue aected (84) (Fig. 2d). The early clinical sign of oral mucositis is diuse erythema, presenting approximately 45 days following chemotherapy or at cumulative doses of head and neck radiation of about 10 Gy. A total of 710 days after chemotherapy or at cumulative doses of 30 Gy, ulcerations can develop in the oro-oesophageal andor gastrointestinal mucosa (77). In the case of chemotherapy-induced mucositis, lesions are observed mostly on the movable mucosa of the buccal mucosa and lateral and ventral surfaces of the tongue, whilst the hard palate and gingival mucosa are rarely involved. Radiation-induced mucositis may involve any radiation-exposed area, including the hard palate. Mucositis associated with chemotherapy lasts approximately 1 week and it generally heals spontaneously approximately 21 days after chemotherapeutic treatment. Radiation-induced mucositis is present for at least 2 weeks following the completion of radiotherapy.
Association with vesiculo-bullous lesions

Most conditions characterized by vesiculae or bullae usually appear as mouth mucosal ulcerserosions due to oral traumatisms. Infectious, idiopathic and autoimmune vesiculo-bullous diseases may have a protracted clinical course, although in the majority of cases, they show a recurrent, yet acute, onset. For example, herpetic gingivostomatitis, herpangina, heat foot and mouth disease, as well as erythema multiforme, present as oral vesiculae or bullae which usually heal within 23 weeks (85, 86). In this paper we focus on pictures of autoimmune vesiculo-bullous diseases which give rise to persistent erosiveulcerative lesions, that generally do not heal within 23 weeks. Autoimmune vesiculo-bullous diseases. Pemphigus, from the Greek pemphix (bubble or blister), includes a group of serious and potentially life-threatening autoimmune diseases, characterized by intra-epithelial blistering and aecting mucosal andor cutaneous surfaces (87). Apart from pemphigus vulgaris (PV), the most common form that aects the mouth (88, 89), there are several variants of pemphigus with oral involvement: pemphigus foliaceus, drug-induced pemphigus, IgA pemphigus and paraneoplastic pemphigus (87). On the contrary, the term immune-mediated sub-epithelial blistering diseases (IMSEBD) comprises a large family of skin mucous membrane diseases (bullous pemphigoid, pemphigoid gestationis, lichen planus pemphigoides, mucous membrane pemphigoid, dermatitis herpetiformis Durhing, linear IgA disease, epidermolysis bullosa acquisita), which present similar clinical features as a consequence of subepithelial blistering (9093).

On the basis of clinical appearance, PV, bullous and mucous membrane pemphigoid (BP and MMP respectively), epidermolysis bullosa acquisita (EBA) and linear IgA dermatosis may be indistinguishable (92). The skin and mucosal features of these autoimmune diseases consist of clear, uid-lled vesicles or bullae that rupture to leave an ulcer or erosion. Conversely, inherited EB is readily diagnosed because skin lesions are continually present from childhood and a familiar occurrence is frequent (94). Scarring, restricted oral opening, and ankyloglossia are complications of the more dramatic forms of EB (95). In PV, blisters are exceptionally observed in the oral mucosa (Fig. 3a), whereas the typical oral lesion appears as a painful erosionulcers with an irregular border of necrotic epithelium and partially covered by a fragile membrane (96, 97). The Nikolskij sign is not always positive, but it can be exhibited by applying pressure to the periphery of the blister and extending the lesions laterally (98). BP primarily aects the skin, whereas MMP and its subgroups, including oral pemphigoid (OP) (99101), prevalently involve the oral cavity (Fig. 3b) and conjunctiva; MMP and its subgroups do not rarely result in irreversible sequelae (102, 103). The most frequent presentation of MMP in the mouth has been reported to be desquamative gingivitis (39, 104, 105). In EBA, progressive and recurrent disease in the mucosal tissues can result in irreversible complications, similar to those seen in MMP, including blindness, ankyloglossia and esophageal strictures. Linear IgA dermatosis (LAD) vesicles are typically distributed over the trunk and extremities. A characteristic lesion of Linear IgA dermatosis can resemble a string of pearls, an urticarial plaque surrounded by vesicles. Mucosal involvement in Linear IgA dermatosis is usually observed in the oral cavity and conjunctiva. Destroying ulceration The conditions reported here are characterized by the destruction or ulceration of the tissue. They usually begin as denite ulcers which undergo enlargement, leading to extensive tissue destruction and cavitation. At this stage, oral ulceration is accompanied by intense systemic manifestations including fever, asthenia, and lymphadenopathy. We distinguish between two subtypes of destroying ulcers, on the basis of either acute or gradual onset.
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These ulcerative conditions are characterized by the tendency to progress slowly. However, they tend to enlarge and eventually develop cavitation if untreated. Since malignant neoplasm can produce similar ndings, it is important to investigate the presence of systemic symptoms, such as fever and regional lymphadenopathy, which usually accompany infective ulcers. We can include in this group: syphilis, infectious granulomatous diseases (tuberculosis and actinomycosis) and non-infectious granulomatous disease (sarcoidosis, Wegeners granulomatosis (WG), and midline non-healing granuloma). Nasal-type natural killer T-cell lymphoma may initially appear as single or multiple, indurated, slightly
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Figure 3 (A) Bullous lesions on the dorsum of the tongue in a patient with pemphigus vulgaris. (B) Mucous membrane pemphigoid of the lower lip. (C) Oral lesions, caused by Pseudomonas aeruginosa in a patient with medullary aplasia, similar to those of noma.

raised ulcers, which classically localize near the midline of the palate (6). Ulcer enlargement can lead to palate perforation and ultimately the lesion may progress and destroy the midface before causing death by exsanguinations after erosion of the large blood vessels (6). Syphilis. Syphilis is an infectious disease which can be congenital or acquired; it is caused by Treponema pallidum, an anaerobic lamentous spirochete. Acquired syphilis is a sexually transmitted disease, and genital and oral sex are implicated in its transmission. The oral cavity is the commonest extra-genital site of syphilis infection (106) and oral ulcers can give rise to three stages of syphilis. The mouth is rarely the site of primary syphilis and its involvement is usually the result of orogenital or oroanal contact with an infectious lesion.
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The upper lip is more commonly aected than the lower in males, while in females the lower lip is principally aected. Chancre, the classic primary lesion forming at the site of spirochete entry, is a 12 cm solitary, painless, deep inammation with a red, purple or brown base and irregular raised border. A painless regional lymphadenopathy is often associated with chancre and it heals spontaneously within 36 weeks. Secondary syphilis develops in 25% of patients from untreated primary infections within 46 weeks after the primary lesions. The most characteristic oral lesion comprises mucous patches (white plaques) which present as oval-to-crescenteric erosions or shallow ulcers of about 1 cm diameter, covered by a grey mucoid exudate and with erythematous haloe (107, 108). Secondary

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syphilis also manifests itself with ulcerous-nodular lesions (lues maligna), which give rise to crateriform or shallow ulcers on the gingivae, palate or buccal mucosa with multiple erosions on the hard and soft palates, tongue and lower lip (108). Tertiary oral mucosal lesions are characterized by the gumma, a nodular lesion frequently localized on the hard palate and tongue, which may evolve into ulcerated areas. Infectious granulomatous diseases. Tuberculosis: Tuberculosis is a re-emerging infectious granulomatous disease, caused mainly by Mycobacterium tuberculosis (109). Two other species of mycobacteriae may also cause tuberculosis: Mycobacterium bovis and Mycobacterium africanum (110). Tuberculous lesions of the mouth are either primary or most commonly secondary to pulmonary tuberculosis (111, 112). Although the clinical picture is variable, oral lesions typically consist of a starry ulcer, most commonly localized on the dorsum of the tongue, with undermined edges and a granulating oor (113). The ulcers are usually solitary, painful, ragged and indurated, and they may be confused with a neoplastic ulcer. Non-infectious granulomatous disease. Wegeners granulomatosis: WG is a well-recognized, although uncommon, disease process of unknown origin; oral involvement is rare (114). The most characteristic oral manifestation of WG is strawberry gingivitis and this is often the rst sign of the disease (115). Oral ulcerations also may be a manifestation of WG (116, 117). The lesions are clinically non-specic and they may occur on any mucosal surface. Ulcers can be deep and cause destruction of underlying bone with the development of tooth mobility.
Ulcerations with acute onset and rapid progression

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Diagnosis and differential diagnosis of oral ulcerations

Ulcers, belonging to one of three groups (SIMPLE, COMPLEX and DESTROYING ulcerations) often present overlapping clinical features, and making a correct diagnosis is a challenge to clinicians. To make a correct diagnosis of chronic oral ulcerations, clinicians should evaluate in detail the history and clinical features of the patient. Furthermore, the number (single or multiple), site, shape, gravity of the ulcer(s), character of the edge of the ulcer(s), the appearance of the ulcer(s) base, the induration (i.e. rmness on palpation, which may be indicative of malignancies or traumatic ulceration which persist over time) and conditions of remaining mucosa (white, red or with vesiculo-bullous associated-lesions) should also be carefully evaluated. Finally, palpation and other special investigations of the lymph nodes must be performed as lymphadenopathy of the cervical nodes may be present as infectious or neoplastic disorders. If a systemic cause is suspected, a general physical examination is also required. Signs and symptoms that should be taken into consideration when a systemic background to mouth ulcers is suspected are: skin, ocular and genital lesions (suggestive of vesiculo-bullous diseases or LP), purpura, fever, spontaneous bleeding, recurrent infections, lymphadenopathy, hepatosplenomegaly (suggestive of haematological diseases), a chronic cough (suggestive of tuberculosis or a mycosis), signs or symptoms suggestive of HIVAIDS (diarrhoea, weight loss, fever, malaise, generalized lymphadenopathy, recurrent andor rare infectious diseases). Patients with a systemic background of mouth ulcers may also benet from a specialist referral. In addition to oral and general clinical examinations, other investigations necessary in making a correct diagnosis of the cause of chronic oral ulcers include: 1 a biopsy when: (i) a single oral ulcer persists for more than 2 weeks andor it appears to be indurated; (ii) oral ulcerations associated with skin lesions or lesions in other mucosa, (iii) oral ulcerations which present with systemic signs and symptoms; and (iv) other complex oral ulcers (e.g. associated with white, red or vesiculo-bullous oral lesions); 2 blood tests, which may be useful for excluding possible haematologicaldisorders, HIV infection or diabetes; 3 microbiological and serological tests (when an infectious cause is suspected); 4 imaging, to investigate lesion dimensions and the involvement of adjacent structures.

Some ulcerative conditions, especially when they occur in malnourished or immuno-compromised patients, can lead to a rapid destruction of mucosal tissues and sometimes be fatal. They are mainly represented by noma and deep mycosis. Noma, also known as cancrum oris, is a rare childhood disease that is characterized by orofacial tissue destruction. It usually starts with gingivitis, then extends to the labiogingival fold and the buccal mucosa. Early features include soreness of the mouth, pronounced halitosis, foetid taste, swelling of the lip and cheek, cervical lymphadenopathy, a foul-smelling purulent oral discharge, and a blueblack discolouration of the skin-aected area. A further progression of the lesion, leading to perforation of the cheek, is rapid, occurring in a matter of days in many cases. Sequestration of the exposed bone and teeth occurs spontaneously after separation of the soft tissue slough. Systemic symptoms include fever, tachycardia, high respiratory rate, and anorexia (118, 119) (Fig. 3c). The most common deep mycosis that may manifest itself with oral ulcers, typically in immuno-suppressed patients, is: cryptococcosis (120, 121), aspergillosis, mucormycosis (122, 123), paracoccidioidomycosis (124), sporotrichosis (125) and histoplasmosis. Oral ulcers are typically chronic and painful but non-specic; they progress rapidly, destroying the bone tissue and surrounding facial muscles with the inltration of fungal hyphae.

Conclusion
Chronic or persistent ulcerative lesions commonly occur in the oral mucosa and, despite their dierent aetiology which ranges from minor irritation (e.g. trauma) to malignancies and systemic diseases, they may often
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appear clinically indistinguishable from other conditions. For this reason, the diagnosis of long-standing oral ulcers is particularly problematic for dental practitioners whilst potentially playing a key role in the early diagnosis of a given underlying disease. We believe that our new classication system could represent a simple and eective tool for clinicians when in presence of a persistent oral ulcer. The number of ulcers, shape, persistence, induration, appearance of the ulcer border, appearance of the ulcer base and gravity of the ulcer are undoubtedly the main clinical features to be considered by clinicians. In this paper, we have proposed three major criteria to be considered when approaching a patient with longstanding oral ulcers: (i) the number of ulcers; (ii) the appearance of the surrounding oral mucosa in association with white, red, or vesiculo-bullous lesions; and (iii) the presence of systemic signs and symptoms, concurrent with the involvement of the skin andor other mucosa membranes. Once a provisional diagnosis of simple, complex, or destroying ulceration has been made, laboratory procedures (e.g. blood tests, microbiological and serological investigations), consistent with their respective algorithms and biopsy, can denitively address the diagnostic challenge. We thus propose adopting the S-C-D system as a practical, clinical-based classication for chronic oral ulcerations.

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