Differential diagnosis for oral ulcers
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The table content from Harrison's was in the large truncated section. I have sufficient information from multiple sources to provide a comprehensive differential diagnosis. Let me compile the answer.
Based on Harrison's Principles of Internal Medicine, Cummings Otolaryngology, and Dermatology textbooks, here is a structured differential diagnosis for oral ulcers:
Differential Diagnosis of Oral Ulcers
Ulceration is the most common oral mucosal lesion. The host context, ulcer morphology, distribution, duration, and associated systemic features narrow the differential. Most acute ulcers are painful and self-limited; chronic or painless ulcers require biopsy to exclude malignancy.
1. Recurrent Aphthous Stomatitis (RAS) — Most Common
The most common nontraumatic cause of oral ulceration, affecting 20–40% of the population.
- Minor aphthae (Mikulicz ulcers): <1 cm, shallow, painful, heal in 7–14 days without scarring. Found on non-keratinized mucosa (buccal, labial, floor of mouth).
- Major aphthae (Sutton disease): >1 cm, deeper, may last weeks to months, heal with scarring. Can involve soft palate and tonsillar pillars.
- Herpetiform ulcers: Multiple small (1–3 mm) recurrent ulcers resembling herpes but not virally caused.
Triggers: stress, trauma, NSAIDs, β-blockers, certain foods (nuts, chocolate, tomatoes), menstrual cycle.
2. Infectious Causes
| Organism | Features |
|---|---|
| Herpes simplex virus (HSV-1) | Primary herpetic gingivostomatitis: multiple small vesicles → ulcers, fever, lymphadenopathy. Recurrent (herpes labialis): lip/vermilion border. Key distinction from aphthae: involves keratinized mucosa (hard palate, gingiva). |
| Herpes zoster (VZV) | Unilateral ulcers following trigeminal dermatome |
| Herpangina / Hand-foot-mouth (Coxsackievirus) | Vesicles → ulcers on soft palate/tonsillar pillars (herpangina); palms, soles, mouth (HFMD) |
| Candidiasis | Pseudomembranous (thrush): white plaques that scrape off leaving erythematous/ulcerated base |
| Syphilis | Primary: painless indurated chancre. Secondary: "snail track" mucous patches |
| Gonorrhea | Ulcers of soft palate/pharynx |
| Tuberculosis | Chronic painless ulcer with undermined edges; rare |
| Histoplasmosis / deep fungi | Chronic indolent ulcer, often in immunocompromised |
| Acute necrotizing ulcerative gingivitis (ANUG / Vincent's angina) | Fusobacterium/Treponema; punched-out interdental papillae, fetid breath, pain |
3. Systemic/Immune-Mediated Conditions
| Condition | Oral Features |
|---|---|
| Behçet syndrome | Recurrent painful aphthous-type ulcers (major criterion); also genital ulcers, uveitis |
| Reactive arthritis (Reiter syndrome) | Less painful aphthous-like ulcers; triad of urethritis, arthritis, conjunctivitis |
| Systemic lupus erythematosus (SLE) | Painless or minimally painful ulcers (a classification criterion) |
| Crohn's disease | Aphthous-like ulcers with granulomatous histology; cobblestoning of mucosa |
| Ulcerative colitis | Aphthous ulcers correlate with disease activity |
| Celiac disease | Recurrent aphthae that remit with gluten elimination |
| PFAPA syndrome | Periodic fever + aphthous stomatitis + pharyngitis + cervical adenitis (children) |
| Cyclic neutropenia | Periodic oral ulcers correlating with neutrophil nadirs every ~21 days |
| Sweet syndrome | Aphthous ulcers as part of acute febrile neutrophilic dermatosis |
4. Mucocutaneous / Dermatologic Diseases
| Condition | Features |
|---|---|
| Pemphigus vulgaris | Flaccid bullae → extensive painful ulcers; oral often precedes skin lesions; positive Nikolsky sign |
| Mucous membrane pemphigoid (MMP) | Subepithelial blistering; desquamative gingivitis; can cause scarring |
| Lichen planus | Wickham striae (lacy white pattern); erosive form produces painful ulcers; involves buccal mucosa |
| Erythema multiforme (EM) | Acute painful hemorrhagic lip/oral ulcers + target lesions on skin; often post-HSV or drug-triggered |
| Stevens-Johnson syndrome (SJS) / TEN | Severe mucosal necrosis + skin detachment; drug-induced; life-threatening |
| Linear IgA disease | Similar to MMP; IgA deposits at basement membrane |
5. Traumatic / Irritant
- Mechanical trauma: ill-fitting dentures, sharp teeth, cheek biting (morsicatio buccarum)
- Chemical/thermal burns: aspirin burn, hot foods
- Factitious ulceration: self-inflicted
- Eosinophilic granuloma (traumatic granuloma): large chronic ulcer, typically lateral/ventral tongue; benign, self-limiting
6. Drug-Induced
- NSAIDs, β-blockers, potassium-channel blockers: aphthous-type ulcers
- Nicorandil: large chronic oral ulcers
- mTOR inhibitors (sirolimus, everolimus): oral ulcers; respond to topical dexamethasone
- Chemotherapeutic agents / methotrexate: diffuse mucositis
- Nivolumab / checkpoint inhibitors: immune-mediated stomatitis
7. Malignancy
- Squamous cell carcinoma (SCC): chronic (>2 weeks), relatively painless, indurated edges, non-healing ulcer. High-risk sites: floor of mouth, ventral/lateral tongue, soft palate-tonsillar complex, lower lip. Risk factors: tobacco, alcohol, HPV.
- Lymphoma: may present as oral ulcer, particularly in immunocompromised patients
- Salivary gland tumors: ulceration if malignant and eroding surface mucosa
- Metastatic deposits: rare; jaw/soft tissue metastases from distant primaries
8. HIV/AIDS-Associated
- Large, deep, atypical aphthous ulcers (idiopathic or CMV)
- Oral hairy leukoplakia (EBV): white plaques, lateral tongue, not easily scraped off
- Kaposi's sarcoma: red/purple plaques or ulcers
- Severe candidiasis, deep fungal infections
Key Diagnostic Pointers
| Feature | Suggests |
|---|---|
| Acute, painful, <2 weeks, non-keratinized mucosa | Aphthous stomatitis |
| Keratinized mucosa (hard palate, attached gingiva), vesicles first | HSV |
| Chronic, painless, indurated | SCC (biopsy urgently) |
| Recurrent with systemic features (eyes, genitalia) | Behçet syndrome |
| Bilateral white lacy pattern + erosions | Lichen planus |
| Severe lip/oral hemorrhagic crusting + skin targets | Erythema multiforme |
| Periodic fever cycles | PFAPA or cyclic neutropenia |
| Immunocompromised host | Opportunistic infection, atypical aphthae |
Sources: Harrison's Principles of Internal Medicine 22E; Cummings Otolaryngology Head and Neck Surgery; Dermatology 2-Volume Set 5e (Elsevier); Andrews' Diseases of the Skin; Goldman-Cecil Medicine
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