Generalized Oral Ulcers and Pain Secondary to Erythema Multiforme

Generalized Oral Ulcers and Pain Secondary to Erythema Multiforme

A 52-year-old woman presents with severe intraoral ulceration and oral pain.

She reports that several years earlier, she had been taking cephalexin when severe intraoral ulceration developed. The antibiotic was discontinued and a different agent was prescribed; the lesions re-emerged within 1 week. A year later the patient began therapy with topiramate for obsessive-compulsive disorder (OCD); less severe but generalized oral lesions subsequently developed over the intraoral mucosa and lips.

She now presents with the lesions shown here, a single dermal lesion and oral pain without apparent trigger.

The patient is overweight and hypertensive. She has sleep apnea that is managed via continuous positive airway pressure. She has undergone gastric bypass surgery 3 times, with postsurgical complications at least once. Her medications include metoprolol (for hypertension), gabapentin (for OCD), fluoxetine (for depression), and aspirin.

She has a history of OCD manifested as picking behavior; and stress rated at 4 on a 0 to 10 scale. The patient receives psychotherapy once a week and has been married for 12 years. She reports a “good” marriage.

Figure 1
Figure 1—Note the extensive lesions present on the ventral tongue.


Oral findings. Multiple shallow ulcerations are localized to the inferior tongue and bilateral posterior buccal mucosa (Figures 1-3). The lesions are large, irregularly shaped, gray-yellow, and covered with a subtle pseudomembrane. They extend from the buccal mucosa onto the attached gingival tissue with erosion of the intradental papilla between posterior teeth. There is mild crusting of the upper and lower lips.

Figure 1
Figure 2—The observed lesions are localized to the buccal mucosa and attached gingiva.


Skin findings. A 1-cm relatively round shallow ulcer with erythematous halo and a cyanotic, erosive center is present on the patient’s lateral calf (Figure 3).

Figure 1
Figure 3 — This large oval lesion suggestive of EM with an
erosion and erythematous halo is evident on the lateral calf.


Laboratory tests. The antinuclear antibody titer was normal. The white blood cell count was slightly high at 11,900/µL, with hypochromasia 2+ and an absolute neutrophil count of 9290/µL. The hemoglobin is slightly low at 11.1%; the hematocrit is 35.9%; and mean corpuscular hemoglobin concentration is 31 fL.

Tissue for biopsy is taken from the left buccal mandibular mucosa and the right buccal vestibule.

Histologic examination. Analysis reveals ulceration of the surface epithelium and evidence of fibrin and neutrophils. The epithelium is covered by parakeratin and is proliferative, with confluent rete pegs. Cells and hyperchromatic nuclei are present in the deeper portion of the spinous layer and are interpreted to be reactive to the underlying inflammation and the ulceration. There is evidence of loss of cohesion in these areas. The underlying fibrous connective tissue is infiltrated by neutrophils, lymphocytes, and plasma cells.

Immunofluorescence antibodies stain is negative for IgG, IgA, and IgM. It is also negative with antibodies to C3 and C1q. A strong positive reaction is noted with antibody to fibrinogen and is present along the basement membrane that separates the surface epithelium from the underlying fibrous connective tissue. The fibrinogen is also present around small blood vessels in the superficial lamina propria. The H&E stained frozen section shows a piece of mucosa covered by epithelium with underlying fibrous connective tissue. The epithelium is of variable thickness and shows evidence of focal basal cell degeneration. The underlying fibrous connective tissue is infiltrated by many plasma cells, eosinophils, and lymphocytes. 

The differential diagnosis includes:

• Erythema multiforme
• Pemphigus vulgaris
• Lymphoproliferative disease
• Wegener granulomatosis
• Vegetative erosive lichen planus
• Lichenoid lichen planus
• Comorbid anemia

Intervention. Given the nonspecific biopsy findings (except for the observed “lichenoid reaction”), 5 days of therapy with a methylprednisolone dose pack was initiated without apparent effect on the lesions. A trial of high-dose corticosteroid (60 mg) was then initiated with initial taper to 20 mg; 20 days of therapy at this dosage resulted in reduction in lesion size but continued pathology. Continuation of the corticosteroid at 20 mg resulted in significant improvement over several weeks. An antifungal medication was added to the corticosteroid. A trial of azathioprine (50 mg) was initiated after the corticosteroid was discontinued; a topical corticosteroid and an antifungal medication were also added. With this regimen, the intraoral tissue remained minimally involved and stable.

Diagnosis. The final diagnosis was probable erythema multiforme. A lichenoid drug reaction is also a possible consideration.


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