What are the causes and treatment options for oral ulcers in a general adult population?

Causes of Oral Ulcers

Oral ulcers arise from a diverse range of etiologies including traumatic injury, infections (bacterial, viral, fungal), autoimmune and immunologic disorders, systemic diseases, medications, and malignancies—requiring a systematic diagnostic approach based on ulcer characteristics, duration, and associated symptoms. 1, 2

Classification by Temporal Pattern

Acute Oral Ulcers (Abrupt Onset, Short Duration)

• Traumatic causes include mechanical injury from dental appliances, sharp tooth edges, or accidental biting, as well as physical trauma from thermal burns or chemical injury 2, 3
• Acute necrotizing ulcerative gingivitis presents with rapid-onset painful ulceration of gingival tissues 4, 3
• Allergic reactions and erythema multiforme cause acute multiple ulcerations, often with constitutional symptoms 4, 3
• Viral infections, particularly herpes simplex virus causing "cold sores" or "fever blisters," typically occur on keratinized mucosa (lips, hard palate, gingiva) 4, 3

Recurrent Oral Ulcers (≥4 Episodes Per Year)

• Recurrent aphthous stomatitis (RAS) is the most common cause, presenting in three forms: minor aphthous ulcers (most common), major aphthous ulcers, and herpetiform aphthous ulcers 5, 3
• Herpes simplex virus reactivation causes recurrent vesicles that rupture into ulcers, distinguished from aphthous ulcers by location on keratinized mucosa 4, 3
• Behçet's syndrome manifests as recurrent bipolar aphthosis (oral and genital ulcers), often with ocular and systemic involvement 5, 6
• Postherpetic erythema multiforme causes recurrent episodes triggered by herpes simplex infection 3

Chronic Oral Ulcers (Persistent >2 Weeks)

• Squamous cell carcinoma is the critical diagnosis to exclude in any solitary chronic ulcer, requiring biopsy 2, 3
• Autoimmune bullous diseases including pemphigus vulgaris, mucous membrane pemphigoid, and erosive lichen planus present with chronic ulceration from ruptured bullae 1, 4
• Tuberculosis causes stellate ulcers with undermined edges and clear boundaries, often indicating pulmonary involvement 1, 6
• Deep fungal infections occur particularly in patients with hyperglycemia or immunosuppression 1, 6
• Hematologic malignancies, including nasal-type extranodal NK/T-cell lymphoma and leukemia, can present as persistent necrotic ulcers with yellowish-white pseudomembrane 1, 6

Systemic Disease Associations

Hematologic Disorders

• Anemia (iron, folate, or B12 deficiency) contributes to oral ulceration and requires full blood count evaluation 1, 6
• Leukemia, particularly acute monocytic leukemia, presents with widespread necrotic ulcers when neutrophil counts are severely decreased (neutropenia <2.0%) 1, 6
• Neutropenia from any cause predisposes to severe oral ulceration 6, 3

Gastrointestinal Diseases

• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) frequently manifests with oral ulcers as an extraintestinal manifestation 2, 6
• Celiac disease is associated with recurrent aphthous stomatitis 3

Infectious Diseases

• HIV infection causes oral ulcers through direct viral effects and opportunistic infections, requiring HIV antibody testing in persistent cases 1, 6
• Syphilis can present with oral ulceration at any stage, necessitating syphilis serology examination 1, 6
• Bacterial infections beyond acute necrotizing ulcerative gingivitis can cause ulceration 2, 3

Medication-Related Ulceration

• Drug-induced ulcers occur from various medications and should be considered in the differential diagnosis of chronic ulcers 7, 3

Diagnostic Algorithm

Initial Assessment for All Oral Ulcers

• Determine temporal pattern: acute (<2 weeks), recurrent (≥4 episodes/year), or chronic (>2 weeks) 2, 3
• Assess ulcer characteristics: solitary versus multiple, size, location (keratinized versus non-keratinized mucosa), presence of pseudomembrane, and morphology 1, 2
• Identify triggering factors: trauma, new medications, dietary changes, or systemic symptoms 7, 8
• Evaluate for constitutional symptoms: fever, weight loss, arthritis, or other systemic manifestations 2, 8
• Examine for extraoral involvement: skin lesions, genital ulcers, or ocular symptoms 2, 4

Laboratory Evaluation Before Biopsy

For ulcers persisting >2 weeks or not responding to 1-2 weeks of treatment, obtain the following blood tests: 1, 2

• Full blood count to rule out anemia, leukemia, and neutropenia 1, 6
• Blood coagulation studies to exclude surgical contraindications 1
• Fasting blood glucose to identify diabetes as a susceptibility factor for invasive fungal infection 1, 6
• HIV antibody testing to rule out HIV infection 1, 6
• Syphilis serology to exclude syphilitic ulceration 1, 6
• Serum specific antibodies (Dsg1, Dsg3, BP180, BP230) if bullous diseases are suspected 1, 6

Biopsy Indications and Technique

• Biopsy is essential for any ulcer lasting >2 weeks or not responding to 1-2 weeks of treatment 5, 2
• Multiple biopsies should be performed if ulcers involve different sites with varying morphological characteristics 1, 2
• Adequate biopsy depth and size are critical—small or superficial biopsies may miss important diagnostic features 2
• Special studies including direct immunofluorescence, immunohistochemistry, and T-cell receptor immunophenotyping may be required based on initial histology 1, 2

Specialist Referral

• Refer to oral medicine specialist for persistent ulcers (>2 weeks) or those not responding to 1-2 weeks of treatment 5, 2
• Oral medicine specialists can perform specialized diagnostic procedures, coordinate multidisciplinary care, and manage complex cases 2

Critical Pitfalls to Avoid

• Never assume a solitary chronic ulcer is benign—every solitary ulcer persisting >2 weeks requires biopsy to exclude squamous cell carcinoma 2, 3
• Do not rely solely on topical treatments without establishing a definitive diagnosis for persistent ulcers, as this delays appropriate management 2
• Avoid inadequate biopsies that are too small or superficial, as they may miss critical diagnostic features 2
• Do not overlook systemic causes—persistent or recurrent ulcers may be the first manifestation of underlying hematologic, autoimmune, or infectious diseases 2, 6
• Consider hyperglycemia as a predisposing factor for invasive fungal infections causing oral ulcers 1, 6
• Recognize that pathology reports stating "inflammatory ulcer with lymphocytic infiltration" are nonspecific and may require consultation with superior pathologists or repeat biopsy 1