The HLA-B51 antigen is an important factor in that it confers susceptibility in some populations, although this may not strictly apply across the geographic spectrum.7  The role of T lymphocytes in the pathogenesis of aphthous ulcers is significant in terms of establishing a focal immune dysfunction in which the cytokine tumor necrosis factor (TNF)-α exerts a major effect on endothelial cell adhesion and neutrophil chemotaxis.8  Following local TNF-α upregulation, lymphocytic aggregation leads to the preulcerative phase.  This phase is followed by the ulcerative phase, in which CD4+ cytotoxic suppressor lymphocytes dominate until they are replaced by CD4+ cells in the healing phase.9 

The nature of a specific initiating factor (or factors) remains undefined.  The causative agent could be an endogenous (autoimmune) or exogenous (hyperimmune) antigen or it could be a nonspecific factor (such as trauma) that could involve chemical mediators.  Focal release of a neuropeptide (such as substance P) could mediate lymphocytic infiltration and epithelial necrosis, generating an aphthous ulcer.  Focal release of cytokines may delay healing, which typifies the clinical course of these lesions.

The clinical similarity of oral aphthous ulcers to recurrent herpes simplex virus (HSV) infections has prompted an extensive search for a viral cause, though such a cause has not been substantiated.  Hypersensitivity to bacterial antigens of Streptococcus sanguis has been suggested but this theory has been discarded.  More recently, Hasan et al reported on a possible molecular link between this organism and antibodies to a heat shock protein (hsp 65-kDa) that may cross-react with host cell mitochondrial hsp and produce mucosal pathology.10

Clinical features

Aphthous ulcers typically are classified as minor, major, and herpetiform types.  All types manifest as painful lesions with variable degrees of recurrence from patient to patient.  A minority of patients may note prodromal symptoms of tingling or burning in the area of ulcer formation.  Ulcers are not preceded by a vesicular phase but rather by a very short-lived grayish pseudomembranous alteration.  This alteration is succeeded by rapid ulcer formation, usually over the vestibular and buccal mucosa, ventral tongue, soft palate, fauces, and floor of the mouth.  The attached gingiva and hard palate may be affected (although this is rare), providing an important clinical sign that makes it possible to differentiate between aphthous ulcers and recurrent herpetic ulcers.  Patients with AIDS may develop aphthous-like ulcers at any mucosal site.11

Minor aphthous ulcers

This most frequently encountered form of aphthous ulceration affects approximately 80% of aphthous ulcer patients.12  Lesions usually appear as a painful oval ulcers, less than 1.0 cm in diameter, that are surfaced by a yellow fibrinous membrane—which, in turn, is surrounded by an erythematous halo (Fig. 1).  Multiple oral aphthae may be seen occasionally.  When the lateral or ventral surfaces of the tongue are affected, pain tends to be disproportionate on the surface of the ulcer.  Lesions generally last 7–14 days and heal without scar formation.  Recurrence rates vary from one individual to another, with ulcer-free intervals ranging from a matter of weeks to years.12

Major aphthous ulcers

Major aphthous ulcers (also referred to as periadenitis mucosa necrotica recurrens or Sutton’s disease) are the most severe expression of aphthous stomatitis.  Lesions are larger (>1.0 cm) and more painful, persist longer than minor aphthae, and heal with scar formation (Fig. 2).  Occasionally, patients may experience an unremitting course with significant morbidity; systemic health may be compromised secondary to difficulty in eating and psychological stress.  Movable oral mucosa is affected in the same way as for minor aphthous ulcers. 

Herpetiform aphthous ulcers

This least common form of aphthous ulceration manifests clinically as recurrent crops of tiny ulcers (<0.1 cm) that may coalesce (Fig. 3). Movable mucosa is affected predominantly, although palatal and gingival mucosa also may be affected.  Pain may be considerable and healing generally occurs in one to two weeks.  Herpetiform aphthous ulcers are not preceded by vesicles and exhibit no evidence of virus-infected cells.  Other than the clinical feature of crops of oral ulcers, there has been no finding that can link this disease to a viral infection.  Women are affected more commonly than men, with the onset occurring later than it does for other forms of aphthous ulceration.13

Histopathology

Aphthous ulcers do not require biopsy confirmation; although they demonstrate nonspecific microscopic findings when sampled, all forms of aphthous ulcers demonstrate the same microscopic features.  CD4+ lymphocytes are found in submucosa and perivascular regions in the preulcerative stage.  These cells predominate early but soon are outnumbered by CD8+ lymphocytes as the ulcerative stage develops.  Macrophages and mast cells are common inhabitants of the ulcer bed.14

Differential diagnosis

Secondary (recurrent) oral herpes infection is the major condition to consider as a possible alternative diagnosis to minor aphthous stomatitis.  This infection usually can be distinguished from aphthous ulcers by noting the presence or history of vesicles that preceded ulcer formation, along with observation of crops of lesions involving the attached gingiva and hard palate.  Conversely, there will be an absence of vesicles in cases of aphthous ulceration, while the mucosa of the hard palate and attached gingiva will be spared (see Tables 1 and 2).  Other painful oral ulcerative conditions include traumatic ulcers, pemphigus vulgaris, mucous membrane pemphigoid, and ulcers secondary to neutropenia.

Treatment

Generally speaking, patients with occasional, minimally bothersome, isolated lesions require little to no treatment beyond using a bland mouthrinse (such as sodium bicarbonate in warm water) to maintain cleanliness.  Historically, very occasional and mild episodes have been treated by placing a small amount of silver nitrate onto the ulcer bed; however, this must be done judiciously and sparingly.  For more severe or frequent recurrences, instituted treatment should be designed to provide significant symptomatic relief, although this is not a cure.  Mild episodes of ulceration may be treated with antiseptic mouthrinses; topical nonsteroidal agents, including tetracycline; amlexanox; sucralfate; and topical analgesics, including benzocaine.  Prescription-level drugs that are intended to modulate the inflammatory and immune responses can be very helpful.  Within this class of agents, topically delivered glucocorticosteroids offer the best chance for disease containment.  Systemic steroids are not employed commonly but they may be used for immediate control when a severe episode is present.15

In most cases, a minimal to moderate dose of prednisone for a short period generally is effective, provided there are no medically related contraindications.  A typical regimen might involve 20–40 mg of prednisone daily for one week, followed by taking half the initial dose for another week before discontinuation.  Topical steroids usually are effective and safe and are less likely to have systemic impact compared with systemic corticosteroids.  Recalcitrant, persistent, or focally severe ulceration may require an intralesional corticosteroid injection in the form of triamcinolone.15

Other drugs

In rare cases, when systemic treatment is required and corticosteroids are either ineffective or contraindicated, other drugs (such as pentoxifylline or colchicine) may be justified.  In extreme cases, the use of thalidomide may be considered.  All of these alternatives must be administered in conjunction with the patient’s medical practitioner and followed accordingly.12

Herpes simplex infections

HSV infections are common vesicular eruptions of the skin and mucosa.  They occur in two forms, systemic (or primary) and recurrent (or secondary).  Both forms are self-limited but the recurrent/secondary form is common.  The virus is sequestered within ganglionic tissue in a latent state after the initial or primary infection and between each recurrence.  Given the particular features of this disease, control and symptomatic relief (rather than cure) is the usual goal of treatment.

Following direct exposure by contact, the incubation period ranges from several days to two weeks.  For overt primary disease, a vesiculo-ulcerative eruption typically occurs in the oral and perioral tissues (primary herpetic gingivostomatitis), with the eruptive focus noted at the site of initial contact.16

It is believed that after primary herpetic gingivostomatitis resolves, the virus migrates through some unknown mechanism along the periaxonal sheath of the trigeminal nerve to the trigeminal ganglion, where it remains in a latent or sequestered state.  No infectious virus is produced within the ganglion during latency.

Primary herpetic gingivostomatitis

Primary disease usually is seen in previously uninfected children, although adults who have not been previously exposed to HSV or who fail to mount an appropriate response to a previous infection may be infected.  Approximately 90% of the U.S. urban population is infected by the age of 4.21  Vesicular eruptions may appear on the facial and perioral skin, the vermilion portion of the lips, and the oral mucous membranes.  Intraorally, lesions may appear on any mucosal surface as painful and tender vesicles and ulcerations (Fig. 4), unlike the recurrent form of the disease, in which lesions are confined to the hard palate and gingiva.  In addition to oral lesions, the primary infection is accompanied by fever, arthralgia, malaise, anorexia, headache, and regional lymphadenopathy.

  

Secondary/recurrent herpes simplex infections

Reactivation of the latent virus leads to recurrent or secondary herpes lesions.  Only rarely are seropositive individuals reinfected by an exogenous source.  HSV antibodies are present in a large majority of the population (up to 90%); of those with HSV antibodies, up to 40% develop secondary herpes.21  The pathophysiology of recurrence has been related to a breakdown in immunosurveillance or to an alteration in local inflammatory mediators that allows the virus to replicate (see Table 4).22

 

 

Approximately 85% of patients develop prodromal symptoms that include tingling, burning, or pain at the site where lesions appear (almost always over the attached gingiva and palatal mucosa intraorally or, more commonly, over the labial vermilion or perioral skin) (Fig. 5 and 6).23  Within 24 hours, multiple fragile and short-lived vesicles appear, ultimately unroofing and coalescing to form irregular superficial ulcers.  Lesions heal within one to two weeks and rarely become infected secondarily.  The number of recurrences across the group of affected patients ranges from one per year or less to as many as one per month.  Rate of recurrence appears to decline with age.  The secondary lesions typically occur at or near the same site with each subsequent recurrence. 

 

 

 

Histopathology

Infected keratinocytes that demonstrate the presence of intranuclear viral inclusions may be seen within characteristic intraepithelial vesicles containing an inflammatory exudate.  These inclusions may be single or multiple (the keratinocytes have a homogeneous glassy nuclear quality) and may be found readily on microscopic analysis (Fig. 7).  After several days, superficial ulceration develops, where herpes-infected keratinocytes degenerate and thus are no longer present in either biopsy or cytologic preparations.  Herpes simplex lesions in HIV-positive patients may be co-infected with cytomegalovirus. 

 

 

Differential diagnosis

Clinical features generally are sufficient for diagnosing primary herpetic gingivostomatitis.  A confirmatory viral culture may be performed, although its utility is questionable.  Monoclonal antibodies or DNA in situ hybridization techniques also are available for identifying a specific virus in tissue sections.

Diagnostic overlap may be noted between streptococcal pharyngitis, erythema multiforme, and acute necrotizing ulcerative gingivitis due to similar systemic signs and symptoms coupled with mucosal findings.  More specifically, streptococcal pharyngitis (minus the formation of vesicles preceding ulcer formation) remains an oropharyngeal infection.  In cases of erythema multiforme, ulcerations are larger (usually without a vesicular stage) and only rarely affect the gingiva.  Lesions associated with necrotizing gingivitis tend to be restricted to the gingiva and are not preceded by vesicles; in addition, they typically are painful and malodorous. 

Based on clinical features and patient history, it is possible to confuse recurrent or secondary intraoral herpes with aphthous stomatitis.  The presence of multiple lesions, a vesicular precursor, and rapid ulcer formation over keratinized tissue sites indicate a herpes virus infection.  Aphthous ulcers usually occur only on nonkeratinized mucosa, such as the floor of the mouth, alveolar mucosa, and buccal mucosa.24

 

Treatment

For any drug to be effective, it must be used as soon as possible, generally within 48 hours after the onset of symptoms.  A number of effective antiviral therapies are available, including acyclovir and its analogs.24

Application of topical agents is effective in terms of their ability to interrupt viral replication through inhibition of DNA polymerization (acyclovir, penciclovir) or by interference with the virus adhering to the epithelial cell surface, preventing intracellular entry of virus (docosanol).

Systemic acyclovir (200–400 mg tablets five times per day) or other antiviral agents are marginally effective for the early management of primary oral herpes, while supportive therapy (fluids, rest, oral lavage, analgesics, and antipyretics) remains essential for any primary herpes simplex treatment regimen.

Secondary herpes can be controlled to some degree with systemic antiviral agents.  Recurrences are not prevented but the course and severity of the disease often are affected favorably.  For immunosuppressed patients as well as patients who suffer frequent recurrent disease following dental procedures, prophylactic systemic antivirals such as valacyclovir should be considered, as they are considered safe over a period of many years.25,26 

 

Summary

This article has provided information concerning the appearance, etiology, differential diagnosis, and therapy of common oral mucosal diseases.  Distinguishing these conditions at an anatomic, symptomatic, and treatment level will allow dentists to manage their patients in a more comprehensive fashion.

 

Author information

Dr. Sciubba is in private practice in Baltimore, Maryland, and currently serves as a consultant to the Milton J. Dance Jr. Cancer Center and The Greater Baltimore Medical Center Department of Otolaryngology, Head and Neck Surgery.

 

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