What is the appropriate workup for a patient with recurrent oral ulcers?

Workup of Recurrent Oral Ulcers

Begin with a detailed clinical history documenting ulcer duration, frequency, number, size, shape, and location, followed by a systematic laboratory evaluation that includes complete blood count, nutritional screening, and infectious disease testing, with biopsy reserved for ulcers persisting beyond 2 weeks or showing atypical features. 1

Initial Clinical Assessment

Document specific ulcer characteristics that guide diagnosis:

• Morphology: Well-demarcated, oval/round ulcers with white/yellow pseudomembrane and erythematous halo suggest recurrent aphthous stomatitis 1, 2
• Location: Note whether ulcers occur on keratinized versus non-keratinized mucosa 3
• Pattern: Assess for bipolar aphthosis (oral and genital), which suggests Behçet's syndrome 4
• Local trauma factors: Identify sharp tooth edges, dental appliances, or thermal/chemical injury that may cause traumatic ulceration 1, 5

Obtain a comprehensive history including:

• Systemic symptoms (fever, weight loss, joint pain, skin lesions, genital ulcers, eye involvement) 1, 6
• Complete medication list to identify drug-induced ulceration 2, 4
• Medical conditions including inflammatory bowel disease, HIV, or autoimmune disorders 5, 4
• Nutritional history and dietary restrictions 4

First-Line Laboratory Testing

For any ulcer persisting beyond 2 weeks or not responding to 1-2 weeks of treatment, proceed immediately with comprehensive laboratory workup: 1, 5

• Complete blood count: Screen for anemia, leukemia, neutropenia, and other hematologic disorders 1, 5
• Fasting blood glucose: Identify hyperglycemia predisposing to fungal infections 1, 5
• HIV antibody testing: Essential to exclude HIV-associated ulceration 1, 5
• Syphilis serology: Rule out syphilitic ulcers 1, 5

Second-Line Laboratory Testing

Based on clinical suspicion and initial test results:

• Nutritional deficiency screening: Iron, folate, and vitamin B12 levels, particularly if anemia is present or dietary history suggests deficiency 1, 4
• Autoimmune markers: If clinical features suggest autoimmune disease 1
• Specific antibody testing: Dsg1, Dsg3, BP180, and BP230 antibodies if bullous diseases (pemphigus vulgaris, mucous membrane pemphigoid) are suspected 1, 5
• Coagulation studies: Required before biopsy to exclude bleeding risk 5

Biopsy Indications and Technique

Biopsy is mandatory for ulcers persisting more than 2 weeks despite appropriate treatment: 1, 5

• Multiple biopsies: Obtain if ulcers have different morphological characteristics 1
• Direct immunofluorescence (DIF): Perform for suspected bullous or autoimmune diseases 1, 5
• Adequate tissue sampling: Ensure biopsy is sufficiently deep and includes ulcer edge with adjacent normal tissue to avoid missing diagnostic features 5, 6

Critical pitfall: Neoplastic ulcers, particularly squamous cell carcinoma, can mimic benign ulcerative lesions—never rely solely on clinical appearance for persistent ulcers 6, 4

Additional Workup for Specific Scenarios

If anemia or abnormal blood counts are detected:

• Bone marrow biopsy may be necessary to evaluate for leukemia or other hematologic malignancies 1

If systemic symptoms are present:

• Broader evaluation for inflammatory bowel disease, Behçet's syndrome, or other systemic conditions 1, 4
• Consider gastroenterology referral for suspected IBD-related ulcers 1

If recurrent aphthous stomatitis (≥4 episodes per year):

• Screen for celiac disease, inflammatory bowel disease, and nutritional deficiencies 4
• Evaluate for rare syndromes and immune disorders 4

Specialist Referral Criteria

Refer to oral medicine specialist for: 1, 5

• Ulcers lasting more than 2 weeks
• Ulcers not responding to 1-2 weeks of initial treatment
• Recurrent, severe, or atypical presentations
• Need for multidisciplinary coordination (hematology for blood disorders, gastroenterology for IBD, rheumatology for autoimmune disease)

Common Diagnostic Pitfalls to Avoid

• Never treat persistent ulcers symptomatically without establishing definitive diagnosis—this delays identification of malignancy or serious systemic disease 1, 5
• Inadequate biopsy technique (too small, too superficial) misses critical diagnostic features 1, 5
• Overlooking systemic causes leads to delayed diagnosis and inappropriate management 1, 5
• Relying solely on clinical appearance without appropriate testing for persistent ulcers can miss serious underlying conditions 1