continuing education

Ulcerative and Vesiculobullous
Oral Mucosal Disease

The History
A history which includes the response to four key questions will narrow considerably the differential diagnosis (see Tables 1 and 2). Since in the oral cavity vesicular and bullous lesions quickly become ulcers, it is important to determine whether the non-specific ulcer first appeared as a vesicle (HSV) or bulla (pemphigus, pemphigoid). Events occurring prior to lesion onset, such as trauma or new medications, will also provide insight into possible causes.

Solitary Chronic Ulcer
Although chronic trauma from oral habit, mastication, or an ill-fitting dental prosthesis is the most common cause for a solitary chronic ulcer, malignancy is the most serious condition to consider. The presence of cancer risk factors such as alcohol and tobacco use should raise suspicion and lower threshold for biopsy. Deep ulceration and destruction of adjacent structures are more common with malignancy and infection. Bacterial (TB, syphilis), fungal (cryptococcus, histoplasmosis, Aspergillus, mucormycosis), and viral (cytomegalovirus) infection are uncommon causes for solitary chronic ulcers, occurring typically in immunosuppressed patients. The most common immunological cause is major aphthous which, aside from a history of previous lesions, may be indistinguishable from infectious or neoplastic processes; major aphthae are more common in the posterior mouth and oropharynx. Lesions similar to major aphthae are not uncommon in association with AIDS, typically when CD4 counts are less than 100 cells/mm3, and biopsy or culture is necessary to exclude infectious process. Treatment of major aphthae includes topical (0.5% clobetesol ointment, dexamethasone elixir) steroids or, when lesions are inaccessible, systemic prednisone (1 mg/kg body weight) and other disease-modifying drugs (DMDs). Thalidomide is approved for and very effective in the treatment of HIV-associated major aphthous ulceration. Treatment is summarized in Tables 3 and 4.

Solitary Acute Ulcer
Trauma is again the most common cause and the patient should be questioned about a recent history of masticatory trauma and examined for a local source of injury. Minor aphthous ulceration is the second most common cause for oral ulceration, followed by herpes simplex virus (HSV). Herpetic ulcers and, less commonly, minor aphthae occur as multiple acute lesions; both are self-limiting and heal uneventfully in about two weeks. Both conditions occur as recurrent lesions as well. The primary lesion of herpes is much more severe than the recurrent form, characterized by generalized gingivo-stomatitis, fever, and malaise. Recurrent intraoral HSV occurs more commonly on heavily keratinized mucosa (palate, gingiva), and recurrent extraoral HSV is most common on the lips and peri-oral skin. Minor aphthae occur more commonly on the less-keratinized mucosa (buccal and labial mucosa). Herpetic ulcers generally have an irregular, raised white border whereas aphthae more commonly have a symmetric, flat, erythematous border. When uncertain as to the diagnosis, simple exfoliative cytology will identify HSV based on viral cytopathy. Culture and serology for HSV are less reliable due to poor specificity (70% seroprevalence and asymptomatic "silent" HSV secretion). In addition to the topical steroids listed in Table 4, a new, very effective topical drug due for release in early 1998 is Aphthasol® (amlexanox). Frequent HSV should be treated or prevented with oral acyclovir (2 gm daily) or avoidance of precipitating factors (i.e., SPF 15 applied to peri-oral area before prolonged sun exposure). The first topically-applied FDA-approved medication for recurrent HSV has recently become available (pencyclovir). Palliative treatment with Kaopectate®, 1:1 diclonine:Benadryl or plain Benadryl elixir can be beneficial.

Multiple Acute Primary or Recurrent Ulcers
As shown in Table 3, many causes of acute multiple ulcers also have recurrent forms of the disorder (recurrent minor aphthae and recurrent HSV). Minor aphthae and HSV were discussed in the previous section. Erythema multiforme (EM) must be considered when there is a sudden onset of generalized oral mucosal ulceration, particularly when the labial mucosa is significantly affected. Concomitant history of skin lesions or new medication use support the diagnosis of a hypersensitivity reaction such as erythema multiforme; there is no definitive diagnostic test for EM. Treatment for minor lesions is palliative, for significant lesions systemic prednisone (0.25-0.75 mg/kg body weight) is necessary. It is important to identify whenever possible and avoid the future use of a precipitating medication. Additionally, "silent" shedding of HSV or a history of antecedent recurrent HSV has been shown to be a common precipitating factor for patients who experience recurrent EM. Thus, patients with recurrent EM should be evaluated for fluctuations in HSV antibody titer or prescribed a trial prophylactic course of oral acyclovir (2 gm daily in divided doses). An important consideration must be made for middle-aged patients (>40 years of age) with new-onset frequent aphthae or any patient with a history of severe aphthae. Between 5-15% of patients who experience constant recurrent aphthae, even though individual lesions may come and heal in two weeks' time, may have an underlying hematologic disorder (anemia) or malabsorptive disease (celiac sprue, gluten sensitive enteropathy). Appropriate hematologic, immunologic, and dietary evaluation should be performed. Treatment of identified underlying disorders also leads to resolution of the severe recurrent aphthae. However, the majority of such patients will have no underlying systemic abnormality and present a significant management challenge. Use of topical (ointment or elixir) and systemic steroids is often necessary. Use of other medications such as colchicine, thalidomide, and disease modifying drugs (DMDs) like levamisol, imuran, and dapsone have also been reported as beneficial in uncontrolled case reports. Another uncommon cause for frequent oral aphthae is Behcet's disease. Although it is a rare disorder, when there is a history of aphthae-like ocular and genital lesions, the diagnosis should be considered.

Multiple Chronic Ulcers
Erosive lichen planus (ELP) is the most common cause for multiple chronic intraoral ulcers. Most patients with oral ELP will also have the typical white striae on the oral mucosa (most commonly the buccal mucosa). ELP can involve an intraoral site. While the ulcers of ELP are somewhat deeper than those of pemphigus or pemphigoid, clinically these conditions may be indistinguishable. All three disorders are systemic illnesses; pemphigus and pemphigoid are classic autoimmune disorders with well-characterized antigens and immunopathogenesis. Unfortunately, approximately 60% of patients with pemphigus, cicatricial pemphigoid, and ELP have oral lesions before cutaneous lesions, perhaps due to the greater fragility of the oral epithelium. However, diagnosis is often delayed until skin lesions appear, due in part to when the patient seeks care, as well as the familiarity of the clinician with the differential diagnosis of chronic multiple oral ulcers. With the exception of even more rare disorders such as epidermolysis bullosa, for all intents and purposes there are few other common considerations for chronic multiple ulcers in an otherwise healthy individual. Unlike ELP, lesions of pemphigus and, to a lesser degree, pemphigoid, are precipitated by minor trauma (Nikolsky sign), and both begin as a fluid-filled bulla which quickly erodes into an ulceration which does not heal. Diagnosis requires biopsy for routine hematoxylin and eosin stains as well as direct immunofluorescence (DIF) for associated auto-antibodies. Additional studies and indirect immunofluorescence may also be required. Other mucosal sites may be involved and the patient should be examined by an ophthalmologist to determine conjunctival disease. Treatment for all three disorders requires systemic prednisone or a combination of DMDs such as imuran, dapsone, and cyclophosphamide. More aggressive treatment may be required for patients with recalcitrant disease and consultation with a dermatologist or immunologist is advised.

GO TO TEST

For further information on this topic, call the UMDNJ Division of Oral Medicine at 973-972-3418 or 7211. References used by author are available upon request.

Winter 1998 Table of Contents

HealthState Home