What are the differential diagnoses and management options for mouth ulcers?

Differential Diagnoses for Mouth Ulcers

For mouth ulcers, the differential diagnosis depends critically on whether the presentation is solitary versus multiple, acute versus chronic, and the duration of symptoms—with any ulcer persisting beyond 2 weeks requiring biopsy to exclude malignancy. 1, 2

Classification Framework

Mouth ulcers should be systematically categorized based on three key characteristics that guide diagnosis 2, 3:

Solitary vs. Multiple Ulcers

Solitary chronic ulcers:

• Squamous cell carcinoma (must be excluded via biopsy in any solitary ulcer lasting >2 weeks) 3, 4
• Traumatic ulceration (related to sharp food, dental appliances, or iatrogenic causes) 5
• Necrotizing sialometaplasia (particularly palatal location) 4
• Tuberculosis (stellate ulcers with undermined edges; requires acid-fast bacilli staining and chest imaging) 3
• Deep fungal infections (especially with hyperglycemia or immunosuppression) 3

Multiple ulcers:

• Recurrent aphthous stomatitis (well-demarcated with yellow/white base and erythematous border) 5, 4
• Herpes simplex virus (typically on keratinized mucosa: hard palate, gingiva) 6
• Erosive lichen planus 2, 6
• Autoimmune bullous diseases (pemphigus vulgaris, mucous membrane pemphigoid) 2, 3
• Behçet's syndrome (recurrent bipolar aphthosis) 3, 4

Acute vs. Chronic Presentation

Acute onset (rapid development, short duration):

• Acute necrotizing ulcerative gingivitis 6, 4
• Erythema multiforme 6
• Allergic reactions 6
• Herpangina 5
• Bacterial infections 4

Chronic ulcers (slow onset, insidious progression >2 weeks):

• Malignancy (squamous cell carcinoma, NK/T-cell lymphoma) 3, 4
• Drug-induced ulceration 4
• Crohn's disease (may coincide with abdominal symptoms) 3
• Chronic autoimmune conditions 6

Hematologic and Systemic Disease Associations

Blood disorders:

• Acute leukemia (widespread necrotic ulcers with yellowish-white pseudomembrane; neutrophil percentage <2%) 1, 3
• Anemia (iron, folate, or vitamin B12 deficiency) 1, 4
• Neutropenia 1, 4

Infectious diseases:

• HIV infection (requires antibody testing) 1, 2
• Syphilis (requires serology testing) 1, 2, 3
• Cytomegalovirus (particularly in immunocompromised patients) 3
• Deep fungal infections (associated with diabetes/hyperglycemia) 1, 3

Mandatory Diagnostic Work-Up

Initial Laboratory Testing (Before Biopsy)

The following blood tests are first-line and mandatory for persistent or unexplained oral ulcers: 1, 2

• Full blood count (to exclude leukemia, anemia, neutropenia) 1, 2
• Coagulation studies (to rule out biopsy contraindications) 1
• Fasting blood glucose (diabetes is a susceptibility factor for invasive fungal infection) 1, 2
• HIV antibody testing 1, 2
• Syphilis serology 1, 2
• Serum autoantibodies (Dsg1, Dsg3, BP180, BP230) if bullous disease is suspected 1, 3

Biopsy Indications and Technique

Biopsy is mandatory for: 2, 5

• Any ulcer persisting beyond 2 weeks without clear diagnosis
• Ulcers not responding to 1-2 weeks of appropriate treatment
• Any solitary chronic ulcer (to exclude squamous cell carcinoma)

Critical biopsy considerations: 1

• If ulcers involve multiple sites with different morphological characteristics, perform multiple biopsies
• For suspected bullous diseases, combine histopathology with direct immunofluorescence (DIF), indirect immunofluorescence, and enzyme-linked immunosorbent assay
• For suspected hematopoietic/lymphoid neoplasms (e.g., NK/T-cell lymphoma), add immunohistochemical assay and T-cell receptor immunophenotyping 1, 3

Key Clinical Features to Document

Essential documentation for accurate diagnosis: 2, 3

• Precise location (keratinized vs. non-keratinized mucosa)
• Duration of symptoms
• Size, shape, depth, and number of ulcers
• Presence of vesicles or bullae (may rupture rapidly)
• White/yellow pseudomembrane or surrounding erythema
• Extraoral manifestations (skin, genital, ocular lesions)
• Constitutional symptoms (fever, arthritis, gastrointestinal symptoms)

Critical Pitfalls to Avoid

Never delay biopsy beyond 2 weeks for persistent ulcers, as malignancy and serious systemic diseases (leukemia, lymphoma) must be excluded. 2, 3

Do not overlook systemic associations: 2

• Multiple oral ulcers may indicate Crohn's disease, blood disorders, or autoimmune conditions
• If gastrointestinal symptoms are present, urgent gastroenterology referral for colonoscopy is required 3

Do not misdiagnose based on appearance alone: 5

• A single ulcer may represent early stages of various conditions
• Recurrent aphthous ulceration can mimic other serious conditions

When to Refer

Immediate referral to oral medicine specialist is indicated for: 3

• Ulcers lasting more than 2 weeks
• Ulcers not responding to 1-2 weeks of treatment
• Recurrent, severe, or atypical presentations requiring biopsy or advanced diagnostic testing
• Cases with systemic symptoms suggesting underlying disease

Special considerations in immunocompromised patients: 3

• Consider CMV quantitative PCR
• Obtain fungal markers (1-3-β-D-glucan, galactomannan)
• Use lower threshold for biopsy