Mouth Ulcerations

I. Problem/Condition.

Mouth ulcerations are common complaints in both hospitalized and non-hospitalized patients. Oral ulcers result from damage to the mucosa of the mouth, both the epithelium, and the lamina propria. When confronted by a patient with an oral ulcer, the key, besides treating any underlying discomfort, is to distinguish which represent underlying systemic disease, and which require biopsy for further evaluation.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Acute Oral Ulcerations (present for < 2 weeks):

  • Traumatic (physical, chemical)

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  • Recurrent aphthous stomatitis

  • Viral (HSV, EBV, CMV, HIV)

  • Bacterial (syphilis)

  • Erythema multiforme/SJS/TEN

  • Chemotherapy (mucositis)

Chronic Oral Ulcerations (present for >2 weeks):

  • Drug-Induced (local and systemic)

  • Lichen Planus

  • Pemphigus vulgaris

  • Mucus membrane pemphigoid

  • Lupus Erythematosus

  • Reactive arthritis

  • GI disease (Crohn’s disease, Ulcerative colitis, Celiac disease, nutritional deficiencies)

  • Malignancy (SCC)

B. Describe a diagnostic approach/method to the patient with this problem.

1. Historical information important in the diagnosis of this problem.

  • Is the oral ulceration new, chronic, or relapsing?

  • What is the duration of the ulcer?

  • Is the lesion painful or painless (the latter raising a greater concern for neoplasm)?

  • Does the patient wear any oral devices such as dentures?

  • Has there been any recent exposure to medications (systemic or localized to the mouth)?

  • Does the patient smoke or drink alcohol?

  • Has there been recent sexual activity or travel?

  • Are there family members that have experienced similar oral ulcers?

  • Have there been similar ulcers in other parts of the body or skin?

Inquiry should be made of any known systemic medical issues, and a thorough review of systems, especially focusing on GI complaints, should be performed for undiagnosed systemic disorders.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

The buccal mucosa, tongue, hard palate, gums, and teeth should be inspected. Note should be made of any dental devices and dentures should be removed if present. The oropharynx should be assessed using a tongue depressor. Note the oral ulcer(s) size, location, and any associated features (such as erythema, bleeding, plaques, odor). Using a gloved finger, lesions should be palpated to assess for induration. Palpate for local and diffuse lymphadenopathy. A thorough inspection of the skin for rashes or ulcers, including the genitals, should be conducted.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Many of the local causes of mouth ulcers do not require laboratory or radiographic testing. A concern for herpes virus infection may prompt viral culture. Any suspicion for systemic disorders leading to the oral ulcerations should prompt lab work, and/or disease specific testing.

Pursue biopsy of an oral ulcer if:

  • it is of unknown origin and has no signs of healing after 2 weeks.

  • it has a known etiology but does not respond to appropriate treatment after 2 weeks.

  • it is believed to result from a specific precipitant and does not show signs of healing 2 weeks after removal of the precipitant.

Biopsy should be excisional for small ulcers (<5mm), incisional for large ulcers (>5mm), and must include both the ulcer and perilesional tissue.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Traumatic: Ulcers that form secondary to traumatic injury typically occur in short painful episodes and are characterized by an erythematous halo around a white or yellowish central clear area. Mechanical trauma is the most common etiology of oral ulceration , and frequent causes include cheek biting, tooth abrasion, and ill-fitting dentures. Caustic ulcers are caused by contact of strong acids or alkali with the oral cavity; common things to consider include aspirin (salicylic acid), potassium supplements, bisphosphonates, and trichloroacetic acid – especially if the patient has dysphagia. Excessive heat or cold can also cause injury to oral mucosa, typically on the tongue and hard palate.

Recurrent aphthous stomatitis (RAS): Aphthous ulcers, commonly known as “canker sores,” appear as recurrent painful, well-defined, ovoid lesions that can have a white or greyish pseudomembrane surrounded by an erythematous halo, and are confined to the soft mucosa of the mouth. Aphthous ulcers usually begin in childhood and affect up to 20% of the population. These ulcers are not infectious, though patients will often report a positive family history. Potential precipitating factors for aphthous ulcers include local trauma, stress, hormonal changes (ulcers often subside during pregnancy), and smoking cessation.

Risk factors for aphthous stomatitis include female sex, caucasian race, and higher socioeconomic status. Aphthous ulcers can be divided into three clinical types:

  • Minor aphthous ulcers are less than 5mm in diameter and heal within 7 to 14 days. Lesions are shallow with a grey/yellow membrane. These represent approximately 80% of aphthae.

  • Major aphthous ulcers are large ulcers with irregular deep raised borders which heal slowly over weeks to months. These lesions often scar and patients are rarely free of ulcers. Major aphthous ulcers are uncommon and usually prompt biopsy to rule out neoplasm.

  • Herpiaphthae appear as clusters of multiple pinpoint ulcers which heal completely within a week to month. The name is purely descriptive and not indicative of a viral etiology.

Behcet’s syndrome may present with all or some of the triad of oral ulcers – which resemble RAS, ocular lesions, and genital ulcers. Behcet’s syndrome is described in further detail elsewhere.

Viral: Viral causes of oral lesions appear as initially as vesicles; those rupture, leaving painful ulcers covered by a yellowish membrane. They tend to coalesce to form larger ulcerations.

Herpetic ulcers can arise from infection with HSV-1, HSV-2, or Varicella-Zoster virus. Primary infection with herpes simplex virus can occur anywhere in the oral cavity leading to vesicles, ulcers, and crusting, often in conjunction with systemic symptoms such as fever and malaise. Reactivation of herpes simplex is usually limited to the hard palate and gingiva (or just to the vermillion border of the lip), and is not associated with systemic symptoms. Herpes Zoster (“shingles”) occurs in a dermatomal distribution which may course through the mouth leading to oral ulcerations.

Viral pharyngitis, typically from the Coxsackie A virus, can manifest with oral ulcers which are usually white or grey with a reddish border. Painful oral ulcers occurring in combination with sore throat and fever is often referred to as herpangina. Coxsackie viral infection may also cause a blistering rash on the palms and soles; when combined with oral ulcers, this is commonly referred to as hand-foot-mouth disease.

HIV infection, in its acute form, can manifest with palatal ulcerations; these ulcers may occur simultaneously with a mono-like syndrome, and maculopapular rash. Later in the disease course, patients may also develop large, deep, painful ulcers in the pharyngeal mucosa often caused by opportunistic pathogens (e.g. Klebsiella). Manifestations, and diagnosis of acute HIV are discussed in further detail elsewhere.

EBV can manifest in several different ways, but most commonly presents with fever, oral ulcers, and palatal petechiae as the syndrome of infectious mononucleosis.

CMV tends to cause large, more chronic oral ulcers almost exclusively in immunosuppressed patients.

Bacterial: Syphilis, which can affect both immunocompromised and immunocompetent patients, is caused by the anaerobic spirochete Treponema pallidum, and is associated with skin and mucosal lesions in both the acute and chronic phases. In the acute phase, syphilis presents as a deep non-painful ulcer with heaped up indurated borders and a highly infectious center. When it presents in the oral cavity, it is general a result of orogenital contact during a sexual encounter. Tertiary syphilis is characterized by “gummas,” pain-free ulcerated nodular lesions on the tongue or hard palate. Gonorrhea can also present with oral lesions, ranging from mild erythema to deep painful ulcers.

Erythema multiforme (EM): Although the etiology of EM is not clearly established, it is a vesicobullous mucocutaneous disease believed to be related to infections and drug treatments, and can be life threatening. The types of exudative EM are (in order of decreasing severity): toxic epidermal necrolysis (TEN), EM major / Stevens-Johnson syndrome (SJS), and multiform erythema minor. The minor form is acute, self-limiting, can be recurrent, and involves the lips in almost all cases, healing with scabs. In both the minor and major forms, <10% of the BSA is affected. TEN generally presents with severe mucosal erosions, bullae, and epidermal detachment involving >10% BSA.

Chemotherapy: Chemotherapeutic agents are a well recognized cause of oral ulcerations. Stomatitis arises around the time of initiation of chemotherapy and usually subsides a week after finishing therapy. Given the patient’s immunocompromised state, non-healing ulcers should raise concern for bacterial superinfection.

Drug-Induced: Systemic drugs/medications can cause single, isolated ulcers surrounded by an erythematous halo and are generally located on the side of the tongue. They tend to be resistant to usual treatments. Drugs that have been associated with oral ulcers include some beta-blockers (labetalol), immunosuppressants (mycophenolate), anticholinergic bronchodilators (tiotropium), platelet aggregation inhibitors (clopidogrel), vasodilators, bisphosphonates (alendronate), protease inhibitors, antibiotics, NSAIDs, antiretrovirals, antirheumatics, and antihypertensives (enalapril, captopril). Lesions typically subside when the offending agent is removed.

Lichen Planus (LP): A chronic disease thought to be caused by cytotoxic T cell-mediated attack on basal keratinocytes. It affects the skin and mucosa, appearing in the oral cavity as whitish striae (reticular LP), areas of atrophy, or erosions and painful ulcers. Definitive diagnosis requires biopsy.

Pemphigous vulgaris (PV): This autoimmune-mediated chronic vesiculobullous mucocutaneous disease presents in most cases with oral lesions, and these are often the initial lesions that are seen. Bullae, appearing in the posterior oral cavity, rupture easily, and form painful ulcers with a necrotic base and erythematous halo. Biopsy is required for diagnosis.

Mucus membrane pemphigoid: An immunological disease primarily affecting the mucosa, and characterized by the spontaneous onset of subepithelial bullae, especially on the palate and gingiva, that rupture and form painful ulcerated areas.

Lupus erythematosus: Lupus can cause oral ulcerations which may foreshadow a systemic disease flare. Patients with discoid lupus have higher rates of oral ulcerations, with most occurring on the buccal mucosa. Systemic Lupus Erythematosus is described in further detail elsewhere.

Reactive arthritis / Seronegative spondyloarthropathies: Seronegative spondyloarthropathies, particularly reactive arthritis (formerly referred to as Retier’s syndrome), can cause painless shallow ulcers on the lips, and in the oral cavity that resemble the ulcers of RAS.

GI diseases: Superficial ulcerations, similar to lesions seen in RAS, can also be a feature of dermatitis herpetiformis, the skin lesions associated with Celiac disease and gluten-sensitive enteropathy. Crohn’s disease, one of the inflammatory bowel diseases, can present with persistent, solitary oral ulcers, varying in prevalence from 5-20%. Two types of ulcers are seen: superficial oral mucosal ulcers and chronic deep linear ulcers with a rolled edge. Crohn’s disease is described in further detail elsewhere. Oral lesions also arise in active or undiagnosed ulcerative colitis, another type of inflammatory bowel disease. These ulcers can look like RAS, or resemble multiple pustules on the soft palate and oral vestibules, a phenomenon called pyostomatitis vegetans. Ulcerative colitis is discussed in further detail elsewhere.

Malignancy: Neoplasm often presents as a slow-growing, painless, non-healing ulcer with raised borders. Squamous cell carcinoma accounts for approximately 90% of all oral neoplasia. Spread of disease occurs along the submandibular and cervical lymph node chains. Tobacco and alcohol use are common risk factors, which can act synergistically to increase the risk of malignancy.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Minor apthous stomatitis is a very common cause of recurrent, painful oral ulceration. Appropriate history taking can often take the place of unnecessary viral cultures or immune serologies. Acute lesions, or lesions with appropriate healing 2 weeks after presentation, do not usually necessitate biopsy.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Mouth Ulcerations.

Management of mechanical trauma should focus on identification, and removal of the offending oral lesion or device (often ill-fitting dentures or poor/mal-aligned dentition). Similarly, management of chemical ulceration should focus on prevention of exposure to the offending agent(s).

Aphthous ulcers are often managed expectantly with counseling that they will heal without intervention. A search for common precipitating factors may help decrease recurrences. Local anesthetic agents or coating agents can provide symptomatic relief. Topical steroid preparations in gel formulation may decrease healing time in some patients; risk of immunosuppression, and alteration of the hypothalamic-pituitary axis vary with potency, frequency of application, and length of topical steroid administration. Systemic therapies aimed at hastening resolution, and decreasing disease recurrence, have been described and typically involve pentoxifylline, colchicine, thalidomide, and oral corticosteroids. A 2012 Cochrane review looking at 25 trials of therapies for RAS determined that evidence for the effectiveness of any single therapy remains inconclusive. Systemic therapy for aphthous stomatitis should likely be done under expert guidance, as the risks of many of the aforementioned agents may outweigh the benefits.

Herpetic viral ulcerations should be dealt with along similar guidelines for treatment of symptomatic or recurrent herpes simplex or zoster infections described in further detail elsewhere.

Management of systemic causes of oral ulceration should focus on recognition of the underlying condition and implementing disease specific therapy.

Concern for neoplasm should lead to referral for prompt biopsy of the lesion.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.


IV. What's the evidence?

Brocklehurst, P, Tickle, MF, FAU, GA, FAU, LM, FAU, PM, Taylor, JF. “Systemic interventions for recurrent aphthous stomatitis (mouth ulcers)”. The Cochrane database of systematic reviews.

Munoz-Corcuera, M, Esparza-Gomez, G FAU, Gonzalez-Moles, M.A., Gonzalez-Moles, MF, Bascones-Martinez, A.. “Oral ulcers: clinical aspects. A tool for dermatologists. Part II. Chronic ulcers”. Clinical and experimental dermatology.

Munoz-Corcuera, M, Esparza-Gomez, G FAU, Gonzalez-Moles, M.A., Gonzalez-Moles, MF, Bascones-Martinez, A.. “Oral ulcers: clinical aspects. A tool for dermatologists. Part I. Acute ulcers”. Clinical and experimental dermatology.

Paleri, V, Staines, KF, Sloan, PF, Douglas, AF, Wilson, J.. “Evaluation of oral ulceration in primary care”. BMJ (Clinical research ed.).

Siu, A, Landon, K, Ramos, DM.. “Differential diagnosis and management of oral ulcers”. Seminars in cutaneous medicine and surgery.