What is the differential diagnosis for a patient presenting with mouth ulcers, considering age, immune status, and oral health history?

Differential Diagnosis of Mouth Ulcers

Mouth ulcers require systematic categorization based on presentation pattern (solitary vs. multiple), duration (acute vs. chronic), and associated features, with any solitary ulcer persisting beyond 2 weeks requiring biopsy to exclude malignancy. 1, 2

Classification by Presentation Pattern

Solitary Ulcers

• Traumatic ulcers from sharp food, dental appliances, or accidental biting correspond in location and shape to the inciting factor and typically resolve within 2 weeks once the trauma source is eliminated 2
• Squamous cell carcinoma must be excluded in any solitary ulcer persisting >2 weeks, particularly in patients >40 years with tobacco use, alcohol abuse, or immunocompromised status 3, 1, 4
• Medication-induced ulceration (e.g., doxycycline, NSAIDs) presents as 1-2 well-marked ulcerations and requires medication history review 3, 2
• Syphilis can present with oral ulceration requiring syphilis serology examination 1
• Tuberculosis causes stellate ulcers with undermined edges and clear boundaries, potentially indicating pulmonary tuberculosis 1

Multiple Acute Ulcers (Rapid Onset)

• Acute necrotizing ulcerative gingivitis presents with rapid-onset multiple ulcers 4
• Herpes simplex virus (HSV) causes shallow ulcers, typically on keratinized mucosa (lips, hard palate, gingiva), often with prodromal symptoms 3, 4, 5
• Allergic reactions and erythema multiforme cause rapid-onset multiple oral ulcers 4
• Candidal esophagitis/stomatitis presents with whitish nummular lesions, particularly in patients with recent antibiotic use or immunosuppression 3, 6

Multiple Recurrent/Chronic Ulcers

• Recurrent aphthous stomatitis (canker sores) is the most common ulcerative condition, occurring on non-keratinized mucosa (buccal mucosa, floor of mouth, soft palate) 5, 7
• Behçet's disease manifests as recurrent bipolar aphthosis with both oral and genital ulcers 2
• Erosive lichen planus presents as lacy reticulations or oral erosions and ulcerations, occurring in up to 2% of individuals 4, 5
• Mucous membrane pemphigoid and pemphigus vulgaris are bullous diseases requiring evaluation for serum specific antibodies (Dsg1, Dsg3, BP180, BP230) and direct immunofluorescence showing IgG and C3 deposition 3, 1, 4

Systemic Disease Associations

Hematologic Disorders

• Anemia and leukemia can present with oral ulcers, requiring full blood count, bone marrow biopsy, and immunotyping 1
• Neutropenia may present with widespread necrotic ulcers with yellowish-white pseudomembrane 1
• Iron and folate deficiencies contribute to oral ulceration 1

Gastrointestinal Diseases

• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) commonly causes oral ulceration and requires specific investigation when ulcers are recurrent and unexplained 3, 1, 2
• Crohn's disease can present with varied presentations including ulcerations 3

Autoimmune/Connective Tissue Diseases

• Scleroderma may show esophageal involvement with dilation and reflux changes 3
• Sjögren's disease can present with nonspecific edema and crepe paper-appearing tissue 3
• Lupus and mixed connective tissue disease can have oral manifestations 3

Infectious Causes

• HIV infection can manifest with oral ulcers, requiring HIV antibody testing in persistent cases 1
• Cytomegalovirus (CMV) causes deep ulceration(s), particularly in immunosuppressed patients 3
• Deep fungal infections occur particularly in patients with hyperglycemia and can cause persistent oral ulcers 1, 2

Diagnostic Algorithm

Initial Assessment

• Age >40 years, tobacco use, alcohol abuse, or immunocompromised status increases suspicion for malignancy 3
• Location matters: HSV typically affects keratinized mucosa while aphthous ulcers occur on non-keratinized mucosa 4, 5
• Duration is critical: ulcers persisting >2 weeks or not responding to 1-2 weeks of treatment require specialist referral 1, 8

Required Testing for Persistent Ulcers

• Blood tests should include full blood count, coagulation, fasting blood glucose, HIV antibody, syphilis serology, and nutritional markers (B vitamins, iron, folate) 1, 2
• Biopsy is essential for persistent ulcers, with consideration for multiple biopsies if ulcers involve different sites with varying morphological characteristics 1, 8
• Special tests including direct immunofluorescence, serum antibody tests, and microbiological cultures may be necessary for definitive diagnosis 1, 8

Critical Pitfalls to Avoid

• Inadequate biopsy (small or superficial) may miss important diagnostic features, particularly malignancy 1, 8
• Overlooking systemic causes leads to delayed diagnosis and inappropriate management 1, 8
• Relying solely on topical treatments without establishing definitive diagnosis for persistent ulcers delays identification of malignancy or systemic disease 1, 8, 2
• Incomplete oral examination including failure to remove dentures, examine lateral tongue with gauze, or visualize oropharynx without tongue protrusion limits diagnostic accuracy 3