Eosinophilic Ulcer 

Updated: Apr 10, 2017
Author: Marc Zachary Handler, MD; Chief Editor: Jeff Burgess, DDS, MSD 

Overview

Practice Essentials

Eosinophilic ulcers are self-limited. They often result from oral trauma. The tongue is the most frequent location of occurrence.

Background

Ulcerations of the oral mucosa are relatively common clinical findings. Oral ulcers may be related to the following:

  • Trauma (eg, physical, chemical, thermal)

  • Aphthous stomatitis

  • Infectious agents (eg, viral, bacterial, fungal, mycobacterial)

  • Contact or systemic allergy (eg, allergy to medication)

  • Neoplastic disease

  • Systemic diseases (eg, hematologic and autoimmune disorders, vasculitides)

Traumatic oral ulcers tend to have a sudden onset and usually heal within a few days or weeks, often without clinical intervention. Occasionally, ulcers may persist for an extended time. Eosinophilic ulcers are included in this group of nonhealing traumatic ulcers. These lesions are microscopically characterized by a diffuse, pseudoinvasive, mixed inflammatory reaction that includes large mononuclear cells, numerous eosinophils, and T cells. The cellular infiltrate often extends deep into the submucosa to involve the underlying skeletal muscle.[1, 2]

Riga-Fede disease is a form of eosinophilic ulcer that develops in infants and usually occurs on the anterior ventral side of the tongue.[3] The distinctive, self-limiting ulcerations develop as a result of chronic mucosal trauma from adjacent anterior primary teeth and usually occur in association with breastfeeding.

Pathophysiology

In most patients with eosinophilic ulcers, trauma is the etiologic factor, and the apparent source of irritation is easily identified. This mechanism is further supported by findings in rats in which microscopically similar lesions were experimentally induced by chronic mechanical injury.[4] However, in a number of studies, patients with multiple synchronous or metachronous lesions at different mucosal sites were identified. The source of the chronic irritation also is not evident in a number of patients; therefore, factors other than trauma may be involved in the pathogenesis of these ulcers. Eosinophilic ulcer has also been reported to occur in association with medication use; therefore, eosinophilic ulcer also may represent an unusual manifestation of a drug reaction.

The eosinophil presence is not fully understood, as most traumatic ulcers do not develop an eosinophilic infiltrate. Several investigators have proposed that eosinophilic ulcers develop as a result of a T-cell–mediated immune response. In certain predisposed individuals, recurrent trauma may lead to the alteration of tissue antigens or ingress of unknown factors (eg, viral particles, toxic microbial products), which result in a hypersensitivity or allergic reaction.[5] However, neither virally altered cells nor viral DNA is identified in biopsy specimens of typical eosinophilic ulcer.

Tissue eosinophilia is not uncommonly associated with T-cell–mediated immune reactions. Activated T lymphocytes produce a variety of lymphokines that are involved in eosinophilic maturation and act as eosinophil-chemotactic factors. Damage and degeneration of mucosal tissues may be due to a proliferation of cytotoxic T cells or toxic products released by degranulating eosinophils. Constituents of eosinophil secretory granules include a number of highly cytotoxic proteins, including eosinophil cationic protein, major basic protein, and eosinophil-derived neurotoxin.

One study demonstrated that, in most eosinophilic ulcer, the synthesis of transforming growth factor-alpha and transforming growth factor-beta is not increased in infiltrating eosinophils.[6] This observation is in contrast to that of the animal wound-healing model, in which eosinophils that express transforming growth factor are typically recruited to healing tissue sites. These findings may help explain the delayed healing that is characteristic of eosinophilic ulcer.

Eosinophilic ulcer, tumorlike eosinophilic granuloma of the skin, and transient eosinophilic nodulomatosis have been suggested to represent a mucocutaneous reaction pattern[7] ; thus, all may share a common pathogenesis.

Epidemiology

Frequency

Eosinophilic ulcers are not uncommon; however, they are infrequently reported in the literature. The frequency with which these lesions develop is unknown.

Sex

The sex prevalence varies from study to study; however, no overall sex predilection is apparent.

Age

Eosinophilic ulcers develop in individuals of all ages, ranging from infants to those aged 92 years. The mean patient age at onset is 46 years. Riga-Fede disease typically is seen in children aged 1 week to 1 year.[8]

Prognosis

The prognosis is excellent, even with conservative treatment. Recurrence is rare; however, the source of the chronic irritation should be eliminated to ensure that the ulcer does not recur. Although certain lesions may behave aggressively, overall, these ulcers do not cause significant morbidity. Occasionally, lesions may demonstrate atypical histologic features. They have been misdiagnosed as lymphoma, and unnecessary radical treatment can result.

 

Presentation

History

The most common complaint is that of an asymptomatic or mildly tender, solitary, nonhealing ulcer of variable duration. The lesion may be present for as short as 1 week or 12 months or longer. Patients with early ulcers often report pain and severe discomfort. Patients may have a history of trauma to the affected area. Depending on the location of the ulcer, other signs and symptoms may include dysphagia, odynophagia, dysphonia, and dyspnea. Occasionally, patients may present with a history of recent weight loss.

Infants with Riga-Fede disease often experience discomfort while breastfeeding, and they may fail to thrive in the postnatal period.

Physical Examination

Eosinophilic ulcers of the mucosa are solitary ulcers with elevated borders of induration. They commonly occur on the lip, tongue, or buccal mucosa. A grayish-pink base is a common feature.[9]

Clinical appearance

Eosinophilic ulcer typically presents as an irregular, solitary ulcer with a fibrinous membrane on the surface. A zone of erythema surrounds the solitary ulcer. The margins of the lesion are often raised and usually indurated. Purulence may be noted emanating from the ulcer.

Eosinophilic ulcers may be a few millimeters to as large as 7-8 cm in greatest dimension.

In rare reports, multiple synchronous or metachronous lesions have been identified.

Occasional ulcers may be macular, whereas others may present as nonspecific erythroplakic or leukoplakic lesions.

In rare cases, an eosinophilic ulcer may present as an elevated, smooth mass that is free of ulceration; however, biopsy reveals the underlying, characteristic, invasive cellular proliferation. In some of these cases, the overlying epithelium may have regenerated without resolution of the underlying inflammation.[9]

Mucosal sites

Any mucosal surface can be affected; however, the tongue is the most common location, accounting for 60% of reported cases.[10, 11] The lateral and dorsal surfaces are usually affected because these are the areas most often traumatized.

Lesions on the ventral surface of the tongue more commonly are observed in infants because of contact with the adjacent mandibular incisors during breastfeeding.

The dorsal surface of the tongue may also be affected in infants because of irritation associated with maxillary incisors. The buccal mucosa and mucobuccal fold are also particularly susceptible to ulceration; lesions in these locations account for 24% of reported cases.

Eosinophilic ulcers have also been reported (in decreasing order of frequency) on the lips, gingiva, palate, floor of the mouth, and retromolar area.

In extremely rare cases, cervical lymphadenopathy is reported.

See the images below.

A 47-year-old African American woman with an eosin A 47-year-old African American woman with an eosinophilic ulcer on the lateral surface of the tongue. The anterior border of the lesion is raised. Courtesy of Dr Paul D. Freedman.
Raised, indurated, nonhealing ulcer on the lateral Raised, indurated, nonhealing ulcer on the lateral surface of the tongue. The lesion was related to an adjacent fractured tooth. Courtesy of Dr Paul D. Freedman.
Ulcer on the ventrolateral surface of the tongue. Ulcer on the ventrolateral surface of the tongue. The differential diagnosis should include squamous cell carcinoma or an infectious etiology. Courtesy of Dr Paul D. Freedman.
Lesion on the lateral surface of the tongue. Court Lesion on the lateral surface of the tongue. Courtesy of Dr Paul D. Freedman.

Causes

Common causes of oral trauma include the following:

  • Self-inflicted injury in which the patient accidentally or deliberately traumatizes the mucosa

  • Injury due to sharp-edged teeth or food

  • Injury due to neonatal or natal teeth (Riga-Fede disease)

  • Toothbrush abrasion

  • Injury due to ill-fitting dentures

  • Injury due to orthodontic or occlusal appliances

  • Iatrogenic injuries (eg, those that occur during dental procedures, such as anesthetic necrosis that occurs during intubation for surgery)

  • Injuries due to accidents

Certain patients may be inherently predisposed to the development of eosinophilic ulcers, although this factor remains controversial.

The role of drug reactions, if any, is unclear.

Medical conditions or therapeutic regimens that predispose an individual to immune suppression may also delay healing.

Complications

If the ulcer does not resolve, even after biopsy and removal, the patient may have an underlying systemic condition that prevents the lesion from healing. The patient should be referred for a medical workup. Pilolli et al emphasize the importance of a differential diagnosis and a thorough evaluation.[12]

Clinicians should remember that deliberate self-mutilation may be a symptom of an underlying emotional disturbance. In cases of self-mutilation, patients may inflict injury to themselves to seek attention and sympathy or to obtain prescription medications. Psychiatric or psychological counseling is often necessary for these patients. Also see Malingering.

 

DDx

Diagnostic Considerations

Also consider noma (necrotizing stomatitis), Epstein-Barr virus infection, and atypical herpes stomatitis (in patients who are immunocompromised).

Occasionally, lesions may demonstrate atypical histologic features. These lesions have been misdiagnosed as non-Hodgkin lymphoma and squamous cell carcinoma, and unnecessary radical treatment may result. Conversely, CD30-positive anaplastic lymphomas have been misdiagnosed as eosinophilic ulcers; therefore, immunohistochemical studies may be needed to confirm the diagnosis.[13]

Differential Diagnoses

 

Workup

Procedures

The clinical presentation and history often suggest the cause and nature of eosinophilic ulcers; however, many cases can resemble ulcerative squamous cell carcinoma. However, if the origin of the lesion is not obvious or if eosinophilic ulcer does not respond to conservative therapy, biopsy under local anesthesia is indicated.

For small lesions, excisional biopsy may be performed; however, incisional biopsy is recommended for larger ulcers.

In general, a biopsy specimen of an eroded or ulcerated area should include a portion of the adjacent intact epithelium.

Histologic Findings

Microscopic sections typically show ulcerated stratified squamous epithelium with underlying granulation tissue characterized by an invasive, dense, mixed cellular infiltrate composed mainly of sheets of large mononuclear cells with pale nuclei and numerous eosinophils.[5] The eosinophils, including many cells that show evidence of degranulation, usually infiltrate deep into the subjacent skeletal muscle, dissecting through and separating the muscle fibers. Degenerating muscle, interfascicular fibrosis, and regenerative myocytes may be identified.

The adjacent surface epithelium may be normal or hyperplastic and occasionally hyperkeratotic. Numerous capillaries, often lined by plump endothelial cells, are usually seen deep to the ulcer. This vascular hyperplasia may lead to surface elevation, which gives the lesion a clinically raised appearance.

Immunohistochemical studies have demonstrated that the large mononuclear cells include two phenotypically distinct cell types: CD68-positive histiocytes and factor-XIIIa–positive submucosal dendrocytes in varying ratios. Longer-standing lesions may have more dendrocytes than histiocytes; however, this finding is controversial.

Typically, small T lymphocytes are scattered throughout the connective tissue, and a minority of these cells are of the CD4 phenotype. Usually, B cells are scarce. Neutrophils are often clustered within and near the base of the ulcer; mast cells, occasional plasma cells, and focally scattered S-100–positive histiocytes also are seen. An increased number of dendritic Langerhans cells may be identified in the epithelium immediately adjacent to the ulcer.

Smooth muscle actin and muscle-specific actin tests usually fail to highlight any of the cells in the connective tissue (except endothelial cells). This finding suggests that myofibroblasts are not an integral component of the cellular proliferation.

Although cellular atypia or mitoses are not typical findings, in rare cases, large atypical cells and mitotic figures may be scattered throughout the cellular infiltrate, creating a pseudolymphomatous pattern. These lesions are termed atypical histiocytic granulomas.[14]

Immunohistochemical studies are often necessary to rule out lymphoma. In some cases, these atypical lesions recur and are subsequently determined to be CD30-positive T-cell non-Hodgkin lymphoma.[13, 15, 16]

The histologic differential diagnosis may include lymphoma, Langerhans cell disease, angiolymphoid hyperplasia with eosinophilia, and Kimura disease. Immunohistochemical studies may be necessary to confirm the diagnosis.

Low-power view showing an ulcerated surface epithe Low-power view showing an ulcerated surface epithelium with a dense cellular inflammatory infiltrate underlying the mucosal surface (original magnification X40). Courtesy of Dr Paul D. Freedman.
Cellular infiltrate composed mainly of large monon Cellular infiltrate composed mainly of large mononuclear cells, including histiocytes and submucosal dendrocytes, eosinophils, and scattered T lymphocytes (original magnification X400). Courtesy of Dr Paul D. Freedman.
Inflammatory infiltrate extending through and betw Inflammatory infiltrate extending through and between muscle bundles (original magnification X400). Courtesy of Dr Paul D. Freedman.
 

Treatment

Medical Care

Dental-related trauma

The source of chronic irritation must be eliminated when an eosinophilic ulcer is due to obvious trauma. Referral to a dentist is recommended if the lesion is related to a tooth, dental restoration, or appliance.

Although extraction of the anterior primary teeth is not recommended, this may resolve the ulcerations in Riga-Fede disease. However, if the teeth are stable, they should be retained. In these cases, breastfeeding should be discontinued, or a protective shield should be constructed to prevent any further trauma. These measures are usually sufficient to resolve the condition.

Palliative care

Nonsteroidal anti-inflammatory drugs (NSAIDs) or topical anesthetics (eg, viscous lidocaine, benzocaine, dyclonine) may be used to provide temporary relief and comfort when the patient eats. A magic mouthwash may also provide symptomatic relief.

Therapeutic care

Some clinicians suggest that the use of corticosteroids may delay healing; however, a mixture of Orabase and a topical corticosteroid ointment (eg, clobetasol, fluocinonide, triamcinolone) is often effective. Dexamethasone elixir is also effective. Although unnecessary, systemic or intralesional corticosteroids may be used.

Surgical Care

As a rule, if the lesion does not resolve or it continues to appear ominous after 2 weeks of treatment, biopsy is warranted. After biopsy, rapid healing of the ulcer is often typical, even with large eosinophilic ulcers, and no further treatment is necessary.

Occasionally, lesions may have to be surgically excised.

Consultations

Consultation with a dentist may be indicated to evaluate and repair fractured teeth or restorations or to alter dentures.

Consultation with an internist may be indicated for the evaluation of an underlying systemic condition in cases in which the ulcer persists, even after biopsy.

Diet

Advise patients to maintain hydration and nourishment. A soft diet is recommended for patients with painful ulcers and to avoid any further irritation. Nutritional supplements, such as Ensure or Boost, may be necessary. Advise patients to avoid eating acidic or spicy foods because they may cause additional discomfort.

Prevention

Patients should eliminate the source of the chronic irritation to prevent recurrence (see Causes).

Long-Term Monitoring

Once treatment is initiated, advise patients to return in 2 weeks for reevaluation. Biopsy is warranted if the lesion does not appear to be resolving with either topical steroid use or removal of the traumatic irritant.

 

Medication

Medication Summary

NSAIDs or topical anesthetics (eg, viscous lidocaine, benzocaine, dyclonine) may be used to provide temporary pain relief and comfort while the patient eats.

Some clinicians suggest that the use of corticosteroids may delay healing; however, a mixture Orabase with a topical corticosteroid ointment (eg, clobetasol, fluocinonide, triamcinolone) often is effective.

Although unnecessary, treatment with systemic prednisone or intralesional injections of triamcinolone has been successful in some patients.

Dexamethasone elixir and magic mouthwash may also provide relief.

Magic mouthwash provides symptomatic relief of stomatitis. Variations of this formulation may be available through a pharmacy or may be personally specified. A standard recipe may include 30 mL diphenhydramine (Benadryl) elixir, 60 mL calcium carbonate and magnesium hydroxide (Mylanta), and 4 g sucralfate (Carafate). Preparations may also include tetracycline (avoid tetracycline if <9 y), attapulgite (Kaopectate), lidocaine, cherry syrup (for children), or hydrocortisone.

Topical anesthetics

Class Summary

These agents may provide temporary symptomatic relief of pain. They also may improve the patient's comfort while eating.

Viscous lidocaine 2% (Xylocaine)

Viscous lidocaine 2% is an anesthetic liquid prescribed to treat painful lesions of the oral mucosa or lips. It inhibits neuronal membrane depolarization, blocking nerve impulses.

For small lesions, apply to the ulcer with a cotton-tipped applicator. It is generally not recommended for use in children because therapeutic doses usually approach potentially toxic levels. If necessary, use the lowest effective dose and supervise children.

Benzocaine (Americaine, Benzocol, Cylex)

Benzocaine inhibits neuronal membrane depolarization, blocking nerve impulses. In pediatric patients, this is a safe alternative to lidocaine.

Dyclonine (Dyclone)

Dyclonine is a ketone local anesthetic agent administered topically. It affects cell membrane permeability and blocks impulses at peripheral nerve endings in mucosa.

Analgesics

Class Summary

Analgesics are used for the relief of mild to moderate pain.

Ibuprofen (Motrin, Advil, Pediaprofen)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Acetaminophen (Tylenol, Tempra, FeverAll, Aspirin-Free Anacin)

Acetaminophen is the drug of choice for pain relief in patients with documented hypersensitivity to aspirin or NSAIDs, those with upper GI tract disease, or those who are taking oral anticoagulants.

Dental aids and preparations

Class Summary

These are topical corticosteroids that share anti-inflammatory, antipruritic, and vasoconstrictive properties. However, they should be mixed with a carrier such as Orabase to ensure adherence of the drug to the mucosal surface. Otherwise, saliva quickly washes away the medication.

Clobetasol (Temovate in Orabase)

Clobetasol is a class I superpotent topical steroid; it suppresses mitosis and increases the synthesis of proteins that decrease inflammation and cause vasoconstriction. Ointment is recommended for intraoral use. Most pharmacists mix 15 g of clobetasol with 15 g of Orabase; this should be indicated on the prescription.

Fluocinonide (Lidex in Orabase)

Fluocinonide is a class II high-potency topical corticosteroid that inhibits cell proliferation; it is  immunosuppressive and anti-inflammatory. Ointment is recommended for intraoral use. Most pharmacists mix 15 g of fluocinonide with 15 g of Orabase; this should be indicated on the prescription.

Triamcinolone topical (Kenalog in Orabase)

Triamcinolone topical is of group III and of intermediate potency. It is used to treat inflammatory mucosal lesions that are responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability. Ointment is recommended for intraoral use. Most pharmacists mix 15 g of triamcinolone with 15 g of Orabase; this should be indicated on the prescription.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Dexamethasone (Decadron, Dexone, Hexadrol, Methasone)

Dexamethasone is an elixir for various allergic and inflammatory diseases. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability. Supervise pediatric patients during administration.

Prednisone (Orasone, Deltasone, Meticorten)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. In most cases, systemic corticosteroids are unnecessary in the management of eosinophilic ulcers. Dividing the dose may increase efficacy, but it also increases the risk of adrenal suppression/adverse effects.