What is the differential diagnosis and treatment for a painful ulcerative oral lesion on the buccal mucosa and palate?

Differential Diagnosis of Painful Ulcerative Oral Lesions on Buccal Mucosa and Palate

For painful ulcerative lesions on the buccal mucosa and palate, the differential diagnosis must systematically exclude malignancy, infection, autoimmune disease, and trauma-related causes through a structured diagnostic approach that prioritizes biopsy for any lesion persisting beyond 2 weeks. 1

Primary Differential Diagnoses

Common Benign Causes

• Recurrent aphthous ulceration presents with well-demarcated ulcers featuring a yellow/white base surrounded by an erythematous border, typically affecting non-keratinized mucosa like the buccal mucosa 2, 3
• Traumatic ulceration results from sharp food, dental appliances, or iatrogenic injury and should be suspected when a clear mechanical cause can be identified 2, 4
• Herpes simplex virus infection manifests as painful ulcerative erosions on the gingiva, palate, buccal mucosa, and tongue, with lesions typically evolving over 10-14 days 5

Serious Conditions Requiring Urgent Exclusion

• Squamous cell carcinoma can present as small ulcerative lesions and must be excluded through biopsy, as malignant transformation occurs at 2-3% annually in potentially malignant disorders 6
• NK/T-cell lymphoma (nasal-type extranodal) presents with serious erosion and necrosis covered by yellowish-white pseudomembrane, confirmed through HE staining and immunohistochemical studies 1
• Oral tuberculosis manifests as widespread ulcers and masses on the palate, requiring identification of granulomatous inflammation with Langhans-type giant cells and acid-fast bacilli on Ziehl-Nielsen staining 1
• Acute leukemia can present with widespread necrotic ulcers covered by smooth, thick yellowish-white pseudomembrane, particularly when neutrophil counts are severely decreased 1

Systemic Disease Manifestations

• Crohn's disease may present with oral ulcers on the buccal mucosa accompanied by abdominal pain, requiring colonoscopy for definitive diagnosis 1
• Invasive fungal infection should be suspected in immunocompromised patients (diabetes, malignancy, immunosuppression) with elevated 1-3-β-D-glucan and galactomannan levels 1
• Behçet's disease features recurrent bipolar aphthosis as its main clinical characteristic 3

Drug-Induced and Iatrogenic Causes

• Stevens-Johnson syndrome/toxic epidermal necrolysis presents with painful mucosal erythema progressing to blistering and ulceration, with tongue and palate frequently affected 1
• Chemotherapy/radiation-induced mucositis causes visible oral and pharyngeal ulcerations, graded by duration and pain severity 1

Mandatory Initial Workup

Pre-Biopsy Laboratory Testing

Before proceeding to biopsy, obtain the following tests to rule out contraindications and provide diagnostic clues: 1, 6

• Full blood count to exclude anemia, leukemia, and neutropenia
• Blood coagulation studies to rule out surgical contraindications
• Fasting blood glucose to identify diabetes (a susceptibility factor for invasive fungal infection)
• HIV antibody and syphilis serology to exclude infectious causes

Critical History Elements

Document the following specific details rather than performing a generic history: 2, 6

• Exact duration, size, shape, and location of the ulcer
• Presence of systemic symptoms including fever, abdominal pain, arthritis, or weight loss
• History of tuberculosis (even if treated years ago, as reactivation can occur)
• Immunosuppression status including diabetes, malignancy, HIV, or immunosuppressive medications
• Tobacco and alcohol use as risk factors for malignancy
• Recent medication changes that could trigger drug-induced ulceration

Biopsy Indications and Technique

Any oral lesion persisting beyond 2 weeks, especially without response to 1-2 weeks of symptomatic treatment, requires biopsy. 6

Biopsy Strategy

• Multiple biopsies should be performed when ulcers involve multiple sites with different morphological characteristics 1
• Excisional biopsy is preferred for small lesions (≤3mm) to allow full histopathologic assessment 6
• Incisional biopsy from the ulcer edge (including adjacent normal tissue) is appropriate for larger lesions 1
• If initial pathology shows only "inflammatory ulcer with lymphocytic infiltration" (a non-specific finding), take paraffin-embedded specimens to superior pathologists for consultation 1

Treatment Approach Based on Diagnosis

For Benign Aphthous Ulceration (After Exclusion of Serious Causes)

Topical treatments constitute first-line therapy: 3

• Topical corticosteroids such as betamethasone sodium phosphate 0.5 mg in 10 mL water as a 3-minute rinse-and-spit preparation four times daily 1
• Clobetasol propionate 0.05% mixed in equal amounts with Orabase, applied directly to affected mucosa daily during acute phase 1
• Topical anesthetics including viscous lidocaine 2% (15 mL per application) or cocaine mouthwashes 2-5% three times daily for severe discomfort 1

For Herpes Simplex Virus Infection

Acyclovir is the treatment of choice: 7

• Dosing: 400 mg orally 5 times daily or 800 mg orally 5 times daily for severe cases
• Duration: Typically 7-10 days
• Bioavailability: 10-20% orally, decreasing with increasing dose; may be administered with or without food 7

For Confirmed Oral Tuberculosis

Four-drug anti-tuberculous therapy is required: 1

• Combination of isoniazid, rifampicin, pyrazinamide, and ethambutol
• Ulcers typically heal and masses resolve after 1 month of treatment

For Stevens-Johnson Syndrome/TEN

Intensive supportive oral care is essential: 1

• White soft paraffin ointment to lips immediately and every 2 hours
• Mucoprotectant mouthwash (e.g., Gelclair) three times daily
• Benzydamine hydrochloride oral rinse or spray every 3 hours, particularly before eating
• Antiseptic oral rinse (1.5% hydrogen peroxide or 0.2% chlorhexidine) twice daily to reduce bacterial colonization

For Systemic Disease-Associated Ulcers

Treatment of the underlying condition is paramount: 1

• Crohn's disease: Oral ulcers resolve with treatment of intestinal disease
• Invasive fungal infection: Caspofungin infusion (except for Zygomycetes and Cryptococci)
• Leukemia: Requires hematology consultation and systemic chemotherapy

Critical Pitfalls to Avoid

Never assume a small or benign-appearing lesion is non-malignant—squamous cell carcinoma can present as small white ulcerative lesions. 6

Do not delay biopsy beyond 2 weeks for any persistent ulcer, as this represents excessive delay in diagnosing potentially life-threatening conditions. 2, 6

Avoid missing synchronous lesions by failing to perform complete oral cavity inspection including all mucosal surfaces, floor of mouth, and oropharynx. 6

Do not overlook systemic disease associations—always inquire about gastrointestinal symptoms, constitutional symptoms, and immunosuppression. 1, 2

If pathology returns as "non-specific inflammation," do not accept this as final—seek expert pathology consultation and consider repeat biopsy. 1