**3. Chronic ulcerative lesions**

Chronic ulcerative lesions have a slower onset than acute ulcers and last for more than two weeks. Several vesiculobullous entities, lupus erythematosus, tuberculosis, some mycoses, eosinophilic ulcers and oral cancer are among the most common conditions associated with chronic oral ulcerative lesions [6].

*Drug induced oral ulcers* are associated with mycophenolate (immunosuppressant), tiotropium (anticholinergic bronchodilator), clopidogrel (platelet aggregation inhibitor), nicorandil (vasodilator), bisphosphonates, protease inhibitors, some antimicrobials and analgesics, antirheumatics and several antihypertensives such as labetalol, enalapril or captopril [30]. This type of ulcerations usually presents with single, isolated ulcers with an erythematous halo. Most commonly the lateral side of the tongue is affected. Once the drug is discontinued, the lesions tend to disappear however it is not always achievable. Drug induced ulcers are also resistant to usual treatments [6].

*Erosive lichen planus* is a subtype lichen planus, a chronic condition which affects both the skin and the mucosal tissues. It is associated with the attack of cytotoxic T-cells on basal keratinocytes, which results in the areas of atrophy, erosion or

#### *Ulcerative Lesions of the Oral Cavity DOI: http://dx.doi.org/10.5772/intechopen.101215*

ulcerations [6]. The World Health Organization considers lichen planus as a premalignant lesion with 1–5% chance of malignant transformation to oral squamous cell carcinoma. Erosive and atrophic forms are particularly considered at high-risk [31]. The most characteristic presentation of lichen planus is the Wickham's striae, which are white, lace-like keratotic mucosal configurations, commonly found bilaterally on the buccal mucosa (**Figure 4**) [32]. Several subtypes of lichen planus may simultaneously manifest in the oral cavity. Erosive lichen planus is one of the painful subtypes due to the ulcerations. These ulcerative lesions are usually covered with a pseudo-membrane and are erythematous (**Figure 5**) [1]. Once lichen planus is confirmed with a biopsy, corticosteroids are prescribed as an initial treatment. Drug resistance is common particularly in erosive lichen planus, thus topical immunosuppressant therapies, such as tacrolimus, aid in the management of this condition via inhibiting cytotoxic T-cell mediated response [6].

*Pemphigus vulgaris* is an autoimmune vesiculobullous mucocutaneous disease due to an IgG reaction against desmogleins which are specific proteins in desmosomes [6]. Almost 90% of the patients experience oral symptoms and in more than half of the cases these are the initial signs of the disease [8]. Clinically oral lesions in

#### **Figure 4.**

*Wickham's striae: The characteristic white, lace-like keratotic configurations seen in lichen planus.*

#### **Figure 5.** *Erosive lichen planus with an ulcerative area covered with a yellowish white pseudomembrane.*

pemphigus vulgaris start as a bulla which quickly raptures in even a slight insult and results in a shallow irregular ulcerative lesion which endures for a long period of time and ultimately involves larger areas of the oral cavity [1, 8]. Ulcerative lesions of pemphigus vulgaris are painful and sometimes bleeding, and they heal with difficulty [8]. Buccal mucosa, palate and the gingival tissues are most commonly affected, and gingival involvement usually manifests as desquamative gingivitis [1]. Biopsy, and direct or indirect immunofluorescence studies confirm the diagnosis. Intraepithelial presence of Tzanck cells is a useful diagnostic sign for pemphigus vulvaris [6]. High dose systemic corticosteroids are used in the treatment of pemphigus vulgaris [1].

*Mucous membrane pemphigoid* or *cicatricial pemphigoid* is another autoimmune vesiculobullous disease that presents with subepithelial bullae which evolve spontaneously and rupture easily, resulting in painful ulcerative areas [6]. Bleeding into bullae results in blood blisters which are among the diagnostic features of mucous membrane pemphigoid [1]. Skin, ocular mucosa, esophagus, nasopharynx and larynx may also be involved besides the oral mucosa. Lesions of mucous membrane pemphigoid are chronic and persistent, thus often heal with a scar (cicatrix) which is particularly observed in lesions of the eye [33]. Contrary to pemphigus vulgaris, palatal mucosa is the most affected area within the oral cavity [6]. Buccal mucosa and the gingiva may also be affected. Gingival lesions in form of desquamative gingivitis may present as the only symptom of mucous membrane pemphigoid in some patients. Depending on the severity of the disease, mucous membrane pemphigoid is initially treated with either topical or systemic corticosteroids, and with dapsone in case of ocular involvement [1].

*Lupus erythematosus* is another autoimmune disorder of the connective tissue. Clinically oral lesions of lupus erythematosus may include areas of well-demarcated erythema, erosion or ulcerations, which tend to bleed. Whitish striae, similar to those seen in the oral manifestations of lichen planus, may also be present on the oral mucosa. Striae in lupus typically involves the hard palate, whereas in lichen planus these lesions are often bilaterally found on the buccal mucosa [6, 32]. Literature contains reports of oral lupus lesions transforming to oral squamous cell carcinoma, therefore it is crucial to regularly monitor and record the symptoms of these patients [34]. Therapeutic options for lupus erythematosus range from antimalarials to non-steroidal anti-inflammatory drugs and glucocorticoids, which may be combined with conventional immunosuppressive agents. Lately targeted therapies such as belimumab or rituximab are also gaining attention [35].

*Linear IgA disease* is also an autoimmune mucocutaneous condition that affects the sub-epithelium. Most patients with linear IgA disease are between 60 and 70 years old, but it may also affect the children. Oral lesions vary from vesicles to painful ulcerations or erosions mostly on the hard or soft palate. Topical or systemic corticosteroids or dapsone may be prescribed depending of the resistance and severity of the lesions [1].

*Tuberculosis* is a bacterial chronic granulomatous disease. Although rare, some tuberculosis patients may experience oral lesions which clinically manifest as solitary, deep, irregular and painful ulcers commonly on the lateral side of the tongue. These ulcers have a rounded rolled border. Final diagnosis is made via a tissue biopsy [1, 6].

*Mycosis-related ulcerative lesions* generally affect immunocompromised or uncontrolled diabetes patients, and present secondary to other infections. Clinical manifestations of different kinds of fungi may vary from painless or painful ulcers with indurated borders, areas of erythema, nodules, granuloma formation or areas of necrosis [1, 6, 36]. It is important to make a histologic evaluation via biopsy with

**Figure 6.** *Typical "crater like lesion with rolled borders"-look on a malignant ulcerative lesion of the hard palate.*

specific stains to accurately diagnose mycoses because the oral symptoms of fungal infections may easily be confused with malignancies. The choice of treatment depends on the type of mycosis and may include antifungal medications with or without surgical intervention [36].

*Eosinophilic ulcer* or *traumatic ulcerative granuloma with stromal eosinophilia* is a benign, solitary ulcer which usually affects patients between fourth and sixth decades of life [1]. Its etiology is not well determined but it is associated with trauma in nearly half of the patients [6]. Viral and toxic agents, eosinophilic cytokines or chemotactic factors, mast cells or other cell-mediated immunity-related factors have also been suggested in the literature. Clinically an eosinophilic ulcer develops rapidly and has elevated borders with a white-yellow fundus [37]. Although it is a self-limiting condition, it heals very slowly and may easily mimic malignancies clinically. Eosinophilrich inflammatory cell infiltrate also consisting of lymphocytes and mast cells help exclude the possibility of a malignancy [6, 37]. These solitary lesions usually respond to surgical excision with a rare recurrence rate. Other treatment modalities include intralesional or oral corticosteroids, topical antibiotics or cryotherapy [1].

*Malignant ulcers* may include epithelial neoplasms, solid tumors like lymphomas or minor salivary gland malignancies. Oral squamous cell carcinoma is the most common malignancy in the oral cavity [8]. It may present as a red white, exophytic, endophytic or ulcerative lesion [6]. Ulcerative lesions are usually asymptomatic and progressive, with a crater-like appearance and rolled, indurated borders (**Figure 6**) [1]. Biopsy is the only reliable method of diagnosis, and the treatment options vary depending on the severity of the disease. Smoking is one of the main risk factors for oral squamous cell carcinoma, therefore these patients must be educated properly and monitored closely for any suspicious lesion [6].

## **4. Recurrent ulcerative lesions**

*Recurrent aphthous stomatitis* (RAS) is painful condition of the non-keratinized mucosa of the oral cavity. It is the most common inflammatory disease of the oral mucosa [1]. RAS has three forms: minor, major and herpetiform. Minor type consists of ulcers with less than 1 cm diameter, whereas the ulcers are larger than 1 cm, long-lasting and they heal with scarring in the major type. Herpetiform type consists of ulcers with less than 2 mm diameter, but the lesions are numerous and extremely painful [1, 3]. Clinically, round and shallow ulcerations occur repeatedly. These ulcers may be solitary or multiple, covered by fibrin and with an erythematous border [1, 8]. Although the true etiology is still unclear, it has been associated with stress, hormonal imbalances, several systemic diseases, certain vitamin or mineral deficiencies [3]. In order to provide a cause-based treatment rather than palliative and temporary management options, it is essential to determine the true cause of RAS. Among the most common causes, iron, zinc, vitamin B12 and folic acid deficiencies, immune disturbances such as either HIV or non-HIV immunodeficiencies, gastrointestinal diseases such as celiac, gluten-sensitive enteropathies, Crohn's or ulcerative colitis, or periodic fever-aphthae-pharyngitis-adenitis syndrome should be questioned, and medical tests should be ordered accordingly. Pain management may be achieved using topical, intralesional or systemic corticosteroids, immunosuppressants or pentoxifylline [3].

*Recurrent herpetic stomatitis* is an oral infection caused by herpes simplex virus and may either manifest as *recurrent herpes labialis*, which affects the lips, or *recurrent intraoral herpes*, which is confined mainly to the keratinized mucosa, especially the hard palate [38]. Low immunity, stress, ultraviolet light, cold weather, hormonal fluctuations or trauma may trigger these lesions [1]. Recurrent intraoral herpes starts as vesicles on the oral mucosa which often rupture and lead to ulcerative lesions. Patient history and clinical examination are important to achieve a correct diagnosis. Once the diagnosis is made, patients should be educated on the contagious nature of the disease. Palliative treatments include ice or lanolin applications, topical or systemic antiviral medications. Prophylactic use of sunscreen with sun protection factor (SPF) 15 or higher may be considered for patients suffering from recurrent herpes labialis [38].

*Herpes-associated erythema multiforme* is a challenging diagnosis which requires a through patient history and clinical evaluation. Erythema multiforme (EM) is a reactive mucocutaneous disorder usually due to hypersensitivity to drugs or other allergens [39]. It may also be induced by other infectious agents like the herpes simplex virus [1, 40]. Herpes-associated erythema multiforme makes up almost the quarter of patients with EM. Herpes-associated EM may proceed simultaneously with or within several weeks after herpes simplex infection [41]. Hemorrhagic crusts on the lips and target lesions on the skin are pathognomonic signs that help make a diagnosis of erythema multiforme [39]. Oral lesions present with macules, blisters or ulcerations. Bleeding and the involvement of the non-keratinized mucosae are common [40]. EM, with mild symptoms, is managed by local wound care, topical anesthetic or analgesic agents, whereas patients with more severe symptoms require oral antihistaminic medications and topical corticosteroids. Herpes-associated EM may successfully be managed with systemic antivirals, if prescribed early. Recurrences are seen in almost 20–25% of patients with a rate of 2–24 recurrences per year [41].

*Cyclic neutropenia* is a lethal condition due to defects in neutrophil maturation which lead to a periodic decrease in neutrophil counts. Gene mutations have been blamed in the etiology of cyclic neutropenia [8, 42]. Recurrent cycles of neutropenia may range from 14 to 35 days and the duration of symptoms also vary between patients [42]. Fever, sore throat, cervical lymphadenopathy, gingivitis, oral ulcerations, tonsillitis, fatigue, otitis media or skin infections are among the most common manifestations of cyclic neutropenia. Ulcers in cyclic neutropenia may either be solitary or multiple, and they heal with scarring [8, 42].

*Behçet's disease* is a systemic immune-mediated vasculitis. The classic triad of Behçet's disease includes oral and genital ulcers, ocular lesions such as uveitis or

### *Ulcerative Lesions of the Oral Cavity DOI: http://dx.doi.org/10.5772/intechopen.101215*

retinal vasculitis, and skin lesions mostly consisting of folliculitis-like rashes, ulcers or erythema nodosum [1, 43]. Recurrences occur at least three times a year. Oral ulcers are present in more than 90% of patients and may sometimes precede other symptoms. The ulcers may be shallow or deep, with slightly raised erythematous borders. They may appear anywhere within the oral cavity and heal spontaneously [44]. Proper management of Behçet's disease should focus on improving the quality of life and maintain the remission of lesions. In case of oral ulcers, pain relief and antiinflammatory applications are aimed. Although there is no gold standard treatment or management method for oral ulcers in Behçet's disease, antimicrobial mouthwashes, laser treatments, topical corticosteroids, or systemic treatment options including colchicine, azathioprine or thalidomide may be considered [45].
