What is the differential diagnosis and recommended work‑up for recurrent aphthous ulcers in a 58‑year‑old man?

Differential Diagnosis and Work-Up for Aphthous Ulcers in a 58-Year-Old Man

Initial Clinical Assessment

For a 58-year-old with aphthous ulcers, begin by determining if these are simple recurrent aphthous stomatitis (RAS) or represent a more serious underlying condition—this distinction is critical because persistent ulcers >2 weeks or those not responding to 1-2 weeks of treatment require biopsy to exclude malignancy and systemic disease. 1

Key Historical Features to Elicit

• Temporal pattern: Determine if ulcers are acute (<2 weeks), recurrent (≥4 episodes/year), or chronic (>2 weeks duration) 2
• Morphology: Assess whether ulcers are well-demarcated, oval/round with white or yellow pseudomembrane and erythematous halo (typical of RAS) versus atypical features 1
• Associated symptoms: Ask specifically about genital ulcers (Behçet's disease), eye symptoms (uveitis), gastrointestinal symptoms (inflammatory bowel disease), and constitutional symptoms 3, 4
• Medication history: Review for NSAIDs and other drugs that can cause oral ulceration 3
• Risk factors: Document smoking history, stress, trauma, family history, and food hypersensitivities 4

Differential Diagnosis

Primary Considerations

• Simple recurrent aphthous stomatitis (RAS): Most common inflammatory ulcerative condition, typically presents with multiple, recurrent, small ulcers with circumscribed margins 5, 6
• Behçet's disease: Recurrent bipolar aphthosis (oral and genital ulcers) with potential eye involvement, particularly posterior uveitis 3, 5, 7
• Inflammatory bowel disease: Commonly causes oral ulceration and should be investigated when ulcers are recurrent and unexplained 3, 4
• Nutritional deficiencies: Iron, folate, or vitamin B12 deficiency can cause oral ulceration 2, 4
• Hematologic disorders: Anemia or leukemia (especially acute monocytic leukemia with neutropenia) can present with oral ulcers 2
• Infectious causes:
  • HIV infection (direct viral effects and opportunistic infections) 2, 4
  • Syphilis (can present at any stage) 2
  • Deep fungal infections (particularly in immunosuppressed or hyperglycemic patients) 3, 2
  • Tuberculosis (stellate ulcers with undermined edges) 1
• Malignancy: Squamous cell carcinoma or lymphoma must be excluded in chronic solitary ulcers 3, 2, 7
• Autoimmune/bullous diseases: Pemphigus vulgaris, mucous membrane pemphigoid 1
• Traumatic ulceration: From dental appliances, sharp teeth, or accidental biting 1, 3

Complex Aphthosis Variants

• MAGIC syndrome: Mouth and genital ulcers with inflamed cartilage 4
• FAPA syndrome: Fever, aphthosis, pharyngitis, and adenitis 4
• Cyclic neutropenia 4

Recommended Work-Up

Initial Laboratory Testing (Before Biopsy)

All patients with persistent or recurrent aphthous ulcers should undergo comprehensive blood testing to exclude systemic causes and establish biopsy safety: 1, 2

• Complete blood count: To detect anemia, leukemia, or neutropenia 1, 2
• Coagulation studies: To exclude biopsy contraindications 1
• Fasting blood glucose: To exclude diabetes (hyperglycemia predisposes to invasive fungal infections) 1, 2
• HIV antibody testing: Essential in persistent cases 1, 2
• Syphilis serology: To rule out syphilitic ulceration 1, 2
• Nutritional markers: Serum iron, folate, and vitamin B12 levels 2, 4
• Serum specific antibodies: If bullous diseases suspected (Dsg1, Dsg3, BP180, BP230) 1

When to Perform Biopsy

Biopsy is mandatory for: 1, 8

• Any ulcer lasting >2 weeks
• Ulcers not responding to 1-2 weeks of treatment
• Solitary chronic ulcers (to exclude malignancy)
• Atypical clinical features

Biopsy technique considerations: 2

• Perform multiple biopsies if ulcers involve different sites with varying morphological characteristics
• Ensure adequate depth and size to avoid missing diagnostic features
• Consider special studies: direct immunofluorescence, immunohistochemistry, T-cell receptor immunophenotyping based on initial histology

Additional Testing Based on Clinical Suspicion

• If inflammatory bowel disease suspected: Gastroenterology referral for endoscopy 3
• If anemia or leukemia suspected: Bone marrow biopsy, immunotyping 1
• If fungal infection suspected: Microbiological cultures 2
• If Behçet's disease suspected: Ophthalmology evaluation for uveitis 5, 9

Specialist Referral Criteria

Refer to oral medicine specialist for: 2, 8

• Persistent ulcers (>2 weeks duration)
• Ulcers not responding to 1-2 weeks of treatment
• Need for specialized diagnostic procedures including biopsy
• Coordination of multidisciplinary care when systemic disease identified

The oral medicine specialist can perform systematic evaluation including detailed clinical history, oral examination, and specialized diagnostic procedures 2

Critical Pitfalls to Avoid

• Never rely solely on topical treatments for persistent ulcers without establishing definitive diagnosis—this delays identification of malignancy or systemic disease 3, 2
• Do not accept nonspecific pathology reports stating "inflammatory ulcer with lymphocytic infiltration" without further investigation; consult superior pathologists or perform repeat biopsy 2
• Do not overlook hyperglycemia as a predisposing factor for invasive fungal infections 2
• Avoid inadequate biopsies (small or superficial) that may miss important diagnostic features 2
• Do not miss systemic causes—overlooking conditions like inflammatory bowel disease, hematologic disorders, or HIV can lead to delayed diagnosis and inappropriate management 2