Leukoplakia

01Pathophysiology

Recurrent aphthous stomatitis (RAS) is the most common inflammatory ulcerative condition of the oral mucosa. The underlying mechanism involves a T-cell-mediated immune response directed against the oral epithelium. In genetically susceptible individuals, various triggers activate CD8+ cytotoxic T lymphocytes and tumor necrosis factor-alpha (TNF-alpha), which cause focal destruction of the mucosal epithelium. This immune-mediated epithelial breakdown is what produces the characteristic shallow, painful ulcer.

The reason these ulcers appear almost exclusively on non-keratinized mucosa (buccal mucosa, labial mucosa, floor of mouth, ventral tongue, soft palate) is that keratinized surfaces such as the attached gingiva, hard palate, and dorsum of the tongue have a thicker protective keratin layer that resists this immune-mediated injury. This anatomical predilection is one of the most testable features of the disease and is the primary way to distinguish aphthous ulcers from herpetic lesions.

The yellow-gray pseudomembrane seen at the ulcer base represents a fibrinous exudate composed of necrotic epithelial cells, fibrin, and inflammatory debris. The surrounding erythematous halo reflects the underlying vasodilation and active inflammatory infiltrate at the ulcer margins. Pain is caused by exposure of subepithelial nerve endings once the epithelial barrier is lost.

Nutritional deficiencies, particularly of iron, vitamin B12, and folate, impair mucosal epithelial turnover and lower the threshold for ulcer formation. This is why correcting these deficiencies can reduce recurrence rates even in the absence of overt anemia. Stress contributes through cortisol-mediated immune dysregulation. Paradoxically, smoking is protective because nicotine promotes mucosal keratinization, which thickens the epithelial barrier against immune attack.

02Classification and Clinical Manifestation

Minor aphthous ulcers are by far the most common subtype and the one most frequently tested. They are small, shallow, and self-limiting. The key teaching point is that they heal without scarring, which differentiates them from major aphthae.

Major aphthous ulcers (also called periadenitis mucosa necrotica recurrens) are deeper, larger, and more painful. They can extend into the submucosa and may involve keratinized tissue, which makes them occasionally confused with squamous cell carcinoma or deep fungal infections. The hallmark is that they heal with scarring.

Herpetiform aphthous ulcers are the most commonly misidentified subtype because their presentation (numerous tiny ulcers that may coalesce) resembles primary herpetic gingivostomatitis. However, despite the name "herpetiform," these ulcers are not caused by herpes simplex virus. The distinction is critical: herpetiform aphthae occur on non-keratinized mucosa and are not preceded by vesicles, whereas true herpetic lesions begin as vesicles on keratinized mucosa.

03Diagnostic Workup

RAS is fundamentally a clinical diagnosis. There is no single laboratory test or imaging study that confirms it. The diagnosis rests on three pillars: (1) the characteristic ulcer morphology (round or oval, yellow-gray base, red halo), (2) location on non-keratinized oral mucosa, and (3) a history of recurrent episodes with symptom-free intervals.

The purpose of the laboratory workup is not to confirm RAS but to exclude underlying systemic conditions that can present with oral aphthae. A CBC with differential is ordered to screen for anemia, neutropenia, or other hematologic abnormalities. Serum iron, ferritin, B12, and folate levels should be checked because deficiencies in any of these are found in up to 20% of patients with recurrent aphthae, and supplementation alone can reduce recurrence.

Celiac disease screening (anti-tTG IgA) is warranted because aphthous stomatitis may be the sole presenting feature of celiac disease, particularly in children. If the ulcers are accompanied by genital ulcers or ocular inflammation, the workup must be expanded to evaluate for Behcet disease, including pathergy testing and ophthalmologic referral.

Biopsy is not routinely indicated. It is reserved for ulcers that fail to heal within the expected timeframe (more than 3 weeks for minor type), ulcers with atypical features (indurated or rolled borders), or when malignancy is suspected. Biopsy of an aphthous ulcer shows nondiagnostic findings: surface ulceration with mixed inflammatory infiltrate. Its value lies entirely in excluding other diagnoses.

04Management and Treatment

First-line treatment for most patients is topical corticosteroids. Triamcinolone acetonide 0.1% in an adhesive dental paste (Orabase) is the standard initial agent. The paste should be applied directly to the dried ulcer surface without rubbing, which allows the medication to adhere to the mucosa. Timing matters: application after meals and before sleep maximizes contact time.

For patients with multiple ulcers or ulcers in areas that are difficult to reach with a paste (posterior oral cavity, soft palate), a corticosteroid mouthwash such as dexamethasone elixir is more practical. The patient rinses and expectorates without swallowing to minimize systemic absorption.

When topical corticosteroids fail or when the patient presents with major aphthous ulcers, escalation to high-potency topical agents (fluocinonide 0.05% or clobetasol 0.05%) is the next step. If these also fail, a short course of systemic prednisone (40 to 60 mg/day with a taper over 1 to 2 weeks) can be used to control an acute flare, but this is not appropriate for long-term management due to adverse effects.

For patients with frequent recurrences requiring maintenance therapy, colchicine (0.6 mg two to three times daily) is a reasonable steroid-sparing option. Its mechanism in RAS is through inhibition of neutrophil chemotaxis and reduction of TNF-alpha. Gastrointestinal intolerance (diarrhea, nausea) is the most common limiting side effect.

Thalidomide (100 to 200 mg daily) is the most effective agent for severe, refractory RAS, particularly in HIV-associated major aphthae. However, it is reserved as a last-resort therapy because of its well-known teratogenicity (absolute contraindication in women of childbearing potential without strict pregnancy prevention programs) and risk of peripheral neuropathy with prolonged use.

An often-overlooked but high-yield management step is nutritional supplementation. Even in the absence of frank anemia, subclinical deficiencies of iron, B12, folate, or zinc can perpetuate the recurrence cycle. Correcting these deficiencies has been shown to reduce both the frequency and severity of episodes.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common mistake on this topic is confusing aphthous ulcers with herpetic ulcers. Test writers exploit this by describing a patient with "multiple small oral ulcers" and relying on students to reflexively select herpes simplex. The discriminator is always location: aphthous ulcers occur on non-keratinized mucosa (buccal mucosa, lips inner surface, floor of mouth, ventral tongue, soft palate), while recurrent herpetic ulcers occur on keratinized mucosa (hard palate, attached gingiva, dorsum of tongue). If the vignette says the ulcer is on the buccal mucosa or the labial mucosa, it is aphthous until proven otherwise.

A second common trap involves the herpetiform subtype. Students see the word "herpetiform" and select herpes as the diagnosis. The name refers only to the morphologic resemblance (numerous tiny ulcers), not to viral etiology. The vignette will emphasize that there are no preceding vesicles and that viral testing is negative.

Another frequently tested concept is recognizing when aphthous ulcers are a clue to a systemic disease. A vignette describing a young patient with recurrent aphthae plus diarrhea and iron deficiency should trigger consideration of celiac disease. A vignette pairing oral ulcers with genital ulcers and eye inflammation points to Behcet disease. Isolated RAS is a diagnosis of exclusion on exam questions when systemic features are present.

Finally, students sometimes overlook the role of nutritional workup. A question may present a patient with recurrent aphthae who has not responded to topical steroids, and the next best step is to check B12, folate, and iron levels rather than escalating to systemic immunosuppression. The core competency being tested is the ability to identify correctable underlying causes before intensifying empiric treatment.