What are the differential diagnoses for multiple ulcers on the tongue?

Differential Diagnoses for Multiple Tongue Ulcers

Multiple ulcers on the tongue require systematic categorization into acute, recurrent, or chronic presentations, with the most common causes including recurrent aphthous stomatitis, herpes simplex virus infection, autoimmune conditions (erosive lichen planus, pemphigus, pemphigoid), traumatic ulceration, and less commonly malignancy, systemic diseases, or opportunistic infections in immunocompromised patients. 1, 2, 3

Acute Multiple Ulcers

Infectious Causes:

• Herpes simplex virus typically presents on keratinized mucosa (hard palate, gingiva) but can affect the tongue, distinguished by rapid-onset vesicles that rupture into multiple small ulcers 3
• Acute necrotizing ulcerative gingivitis causes rapid-onset painful ulceration with characteristic gingival involvement 3
• Herpangina should be considered in the differential, though typically affects the soft palate more than tongue 4

Allergic/Hypersensitivity:

• Erythema multiforme presents with rapid-onset multiple oral ulcers, often with target lesions on skin and constitutional symptoms 3
• Stevens-Johnson syndrome/TEN causes widespread necrotic ulcers with thick yellowish-white pseudomembrane, requiring intensive supportive care including white soft paraffin ointment, mucoprotectant mouthwash, and benzydamine hydrochloride rinse 2

Recurrent Multiple Ulcers

Recurrent aphthous stomatitis is the most common cause of recurrent oral ulcers, presenting as well-demarcated ulcers with yellow/white base and erythematous border on non-keratinized mucosa 4, 3

Chronic Multiple Ulcers

Autoimmune Conditions (require immunofluorescence for diagnosis):

• Erosive lichen planus must be diagnosed using immunofluorescence per International Journal of Oral Science recommendations 1
• Pemphigus vulgaris requires immunofluorescence confirmation 1, 3
• Mucous membrane pemphigoid needs immunofluorescence for definitive diagnosis 1, 3

Malignancy:

• 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 2
• Squamous cell carcinoma can present as multiple small white ulcerative lesions—never assume benign appearance excludes malignancy 2
• Acute leukemia manifests as widespread necrotic ulcers with smooth, thick yellowish-white pseudomembrane, particularly with severe neutropenia 2

Infectious (Chronic/Opportunistic):

• Oral tuberculosis presents as widespread ulcers and masses, requiring identification of granulomatous inflammation with Langhans-type giant cells and acid-fast bacilli on Ziehl-Nielsen staining, treated with four-drug therapy (isoniazid, rifampicin, pyrazinamide, ethambutol) 2
• Disseminated histoplasmosis in HIV patients presents as multiple well-demarcated clean-based ulcers, diagnosed by biopsy showing histiocytes with intracellular yeast forms 5
• Invasive fungal infection particularly in diabetic or immunocompromised patients 2

Systemic Disease Associations:

• Crohn's disease can present with multiple oral ulcers as an extraintestinal manifestation 1
• Blood disorders including anemia and neutropenia 1, 2
• Behçet's disease causes recurrent oral and genital ulcers with ocular involvement 6
• Lupus erythematosus associated with chronic oral ulceration 6

Mandatory Diagnostic Workup

First-Line Laboratory Testing (before biopsy):

• Full blood count to exclude leukemia, anemia, and neutropenia 1, 2
• Fasting blood glucose to identify diabetes 1, 2
• HIV antibody testing 1, 2
• Syphilis serology 1, 2
• Blood coagulation studies to rule out surgical contraindications 2

Biopsy Indications:

• Mandatory if ulcers persist beyond 2 weeks without clear diagnosis—delaying beyond this timeframe is excessive and risks missing malignancy or serious systemic disease 1, 2
• Multiple biopsies are needed when ulcers have different morphological characteristics 1, 2
• Excisional biopsy preferred for small lesions (≤3mm); incisional biopsy from ulcer edge including adjacent normal tissue for larger lesions 2
• Immunofluorescence studies required for suspected erosive lichen planus, pemphigoid, or pemphigus 1

Critical Documentation Requirements

The American Academy of Oral Medicine mandates documenting:

• Precise location of all ulcers 1
• Presence or absence of vesicles or bullae (may rupture rapidly) 1, 3
• Extraoral manifestations including skin, genital, or eye lesions 1, 7
• Duration, size, shape, and growth pattern over time 4, 7
• Constitutional symptoms (fever, arthritis, gastrointestinal symptoms) 2, 7

Critical Pitfalls to Avoid

• Never delay biopsy beyond 2 weeks for persistent ulcers—malignancy and serious systemic diseases must be excluded 1, 2
• Never assume benign appearance excludes malignancy—squamous cell carcinoma can present as small white ulcerative lesions 2
• Never overlook systemic associations—multiple oral ulcers may indicate Crohn's disease, blood disorders, or autoimmune conditions 1, 2
• Never miss synchronous lesions—perform complete oral cavity inspection including all mucosal surfaces, floor of mouth, and oropharynx 2