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A 19-year-old African American female presented to Dr. Paul Seider an Oral & Maxillofacial Surgeon in Tamarac, Florida, for evaluation of oral ulcers. The patient has almost a 10-year history of painful recurrent ulcers throughout her mouth. During each recurrence, the sores last 3 to 4 weeks. She did not remember taking any medications or being exposed to allergic materials that could have triggered the outbreak of ulcers. Intraoral examination revealed diffuse, large, shallow erosions and ulcerations surrounded by irregular erythematous borders on the lateral ventral surfaces of the tongue (Fig. 1), and buccal mucosae (Fig. 2). Hemorrhagic crusting of the vermilion zone of the lips was also noted (Fig. 3). Dr. Seider performed an incisional biopsy. This was then submitted to the University of Florida Oral Pathology Laboratory biopsy service for microscopic examination.

Question

Based on the clinical findings and medical history, what is the most likely diagnosis?

A. Recurrent Aphthous ulcers

B. Behçet’s disease

C. Recurrent or secondary herpes

D. Pemphigus Vulgaris

E. Erythema Multiforme

Diffuse large ulcerations and erosions surrounded by irregular erythematous borders noted on the lateral border of the tongue.

A. Recurrent Aphthous ulcers

Incorrect. Aphthous ulcers are usually seen in young individuals and are very painful. Patients usually report a history of similar outbreaks in the past, as reported by this patient. The ulceration demonstrates a yellow-white, fibrinopurulent membrane which is surrounded by an erythematous halo. The ulcers may be preceded by an erythematous macule in association with prodromal symptoms of burning, itching or stinging. Aphthous ulcers in general occur almost exclusively on non-keratinized mucosa and don’t exhibit hemorrhagic crusting as in this case.

B. Behçet disease

Incorrect, Behçet disease is a vasculitic disorder occurring in the third decade of life and is characterized by episodic apththous ulcers, as seen in the present case. The condition is most common in Turkey, Japan, and the Eastern Mediterranean countries. The exact etiology is unknown, but environmental and genetic factors are implicated in its pathogenesis. The HLA-B51 allele is strongly associated with the disease and is highly prevalent among individuals of Asian descent. Oral ulcers occur in 92% to 100% of patients and are painful. They are similar to the aphthous ulcerations (minor, major, or herpetiform aphthae) occurring in otherwise healthy individuals and demonstrate the same frequency and duration. Aphthous ulcers associated with Behçet disease exhibit a predilection for the soft palate and oropharynx. They typically heal within a couple of weeks. Most importantly, patients with Behçet disease also have skin, genital and ocular lesions which were not present in this patient. The diagnosis of Behçet disease is based on the presence of recurrent oral ulceration (as seen in this patient), plus two of following: recurrent genital ulcers, eye lesions, or skin lesions (features not seen in this case) and a positive pathergy test.

C. Recurrent or secondary herpes

Incorrect, but an excellent choice. The most common site of recurrence for herpes simplex virus-1 is the vermilion border and adjacent skin of lips, which is also known as herpes labialis. The lesions present as multiple small, erythematous papules which may form clusters of fluid-filled vesicles. The vesicles rupture and crust within two days, and healing usually takes place within 7-10 days, which is very much unlike the present case. Majority of the affected patients experience approximately two recurrences annually, but a few may experience outbreaks more frequently.

Patients with rapidly developing recurrences tend to respond less favorably to treatment. Recurrent herpetic lesions, in immunocompetent patients, almost always are limited to keratinized mucosa (bound to the bone) like gingiva and hard palate, which does not fit the pattern of distribution seen in this patient. In immunocompromised patients, intraoral lesions may spread to unbound mucosa, however, this is not the scenario in this case. Moreover, these lesions begin as small vesicles that collapse to form cluster of erythematous macules, and do not present as large ulcerations as seen in this patient.

D. Pemphigus Vulgaris

Incorrect. Pemphigus vulgaris (PV) is an uncommon immune-mediated disease. PV has an estimated prevalence of 30,000 cases in the USA and an incidence of 1–10 new cases per 1 million population. PV is one among the four-pemphigus variants that can affect oral mucosa in addition to pemphigus vegetans, which is considered an extremely rare condition. PV typically affects adults, with an average age of 50 years, and no sex predilection. Rare cases have been reported in childhood. The condition is mostly seen in persons of Mediterranean, South Asian, or Jewish heritage. Oral lesions are often the first sign and precede skin lesions in 50% of cases and are the most difficult to resolve with therapy. Any area of the oral cavity may be involved, however, areas subjected to frictional trauma such as the buccal mucosa, palate, lower lip, and tongue are most affected, as seen in this patient. Clinically, PV oral lesions are painful and appear as superficial, ragged erosions and ulcerations which can cause dysphagia and weight loss. Rarely, patients may report vesicle or bullae formation which rupture quickly, leaving behind raw, and painful ulcerations. Desquamative gingivitis is also a common feature seen in the majority of vesiculobullous conditions, which is another feature not seen in the present case. A positive Nikolsky’s sign is a characteristic feature of PV, in which a new bulla formation can be induced on normal-appearing skin upon slight lateral pressure. No bulla formation or Nikolsky’s sign was noted in this case. Unlike the present case, PV oral lesions are recalcitrant and do not heal in 4 weeks unless treated.

E. Erythema Multiforme

Correct. Erythema multiforme (EM) is a blistering, ulcerative mucocutaneous condition of uncertain etiopathogenesis. It probably represents an immunologically mediated process which is triggered in about 50% of the cases especially in younger individuals by a preceding herpes simplex infection and in older individuals by an exposure to a variety of medications. EM typically has an acute onset and usually affects young adults in their 20s or 30s. Men are affected slightly more than women. The condition is usually self-limiting, lasting 2 to 6 weeks. Prodromal symptoms, like fever, malaise, headache, cough and sore throat, occur about one week before onset. Oral lesions are very painful and begin as round, dusky erythematous patches that ulcerate and evolve into large, shallow erosions and ulcerations with irregular borders, like the ones seen in this patient. Hemorrhagic crusting of the vermilion zone of the lips is usually characteristic, a feature seen in this patient (Figure 3). EM presents with a wide spectrum of clinical disease ranging from ulcerations, erythema, bullae, erosions or nonspecific erythematous changes. Even though the disease is self-limiting, about 20% patients may experience recurrent episodes, just as seen in this patient. In cases of recurrent episodes of EM, initiating factors like recurrent herpes infection or drug exposure should be considered.

Severity is ranging from EM minor, when either skin or mucosal epithelium is involved, through EM major, when both skin and mucosal epithelium are affected. Beside oral mucosa, other mucosal epithelium such as conjunctival, genitourinary and respiratory mucosa also may be affected. With severe ocular involvement, scarring (symblepharon formation) may occur, similar to that in mucous membrane (cicatricial) pemphigoid.

Patients with EM may develop skin lesions which appear as concentric circular erythematous rings resembling a target or bull’s-eye. Cutaneous and other non-oral mucosal lesions were not seen in this patient. When EM is restricted to the oral cavity, it can be mistaken for other inflammatory, vesiculobullous, and dysplastic conditions. Patients may be dehydrated because of the inability to ingest liquids as a result of mouth sores.

EM is often diagnosed clinically. Histology and direct immunofluorescence can help to exclude other vesiculobullous conditions. EM usually has no specific histologic pattern comparing with other vesiculobullous lesions. Oral EM and lichenoid drug eruptions may be virtually indistinguishable except lesions seen in EM lack the characteristic peripheral striae that are seen in lichenoid drug eruption. Also lesions in EM usually eventually heal only to reoccur unlike those in lichenoid drug eruptions which usually resolve after discontinuation of the offending medication(s).

Depending on the extent of the disease, topical or systemic corticosteroids may be used, especially in the early stages of the disease. Steroids tend to show a striking resolution of lesions such as Clobetasol ointment (0.05%). Antiviral therapy is recom- mended, if herpetic infection is considered a triggering factor. If a causative drug is identified or suspected, then it should be discontinued immediately.

References:

1) Cizenski JD, Michel P, Watson IT, Frieder J, Wilder EG, Wright JM, Menter MA. Spectrum of orocutaneous disease associations: Immune-mediated conditions. J Am Acad Dermatol. 2017; 77(5):795806.

2) Thete SG, Kulkarni M, Nikam AP, Mantri T, Umbare D, Satdive S, Kulkarni D. Oral manifestation in patients diagnosed with dermatological diseases. J Contemp Dent Pract. 2017; 18(12):1153-1158.

3) Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current perspectives on Erythema Multiforme. Clin Rev Allergy Immunol. 2018; 54(1):177-184.

4) Arduino PG, Porter SR: Herpes simplex virus type 1 infection: overview on relevant clinicopathological features, J Oral Pathol Med 37:107–121, 2008.

Diagnostic Discussion is contributed by University of Florida College of Dentistry professors, Drs. Indraneel Bhattacharyya, Nadim Islam and Saja Alramadhan who provide insight and feedback on common, important, new and challenging oral diseases.

The dental professors operate a large, multi-state biopsy service. The column’s case studies originate from the more than 14,000 specimens the service receives every year from all over the United States.

Clinicians are invited to submit cases from their own practices. Cases may be used in the “Diagnostic Discussion,” with credit given to the submitter.

Drs. Bhattacharyya, Islam and Alramadhan can be reached at oralpath@dental.ufl.edu.

Conflict of Interest Disclosure: None reported for Drs. Bhattacharyya, Islam and Alramadhan.

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