Oral Ulcer at Ions in a Patient With Severe Asthma

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Faizan AlawiScott S. DeRossi, Katharine N. Ciarrocca andasthmaOral ulcerations in a patient with severe

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Oral ulcerations in a patient

with severe asthmaScott S. DeRossi, DMD; Katharine N. Ciarrocca, DMD, MSEd; Faizan Alawi, DDS

CLINICAL PRACTICE DIAGNOSTIC CHALLENGE

JADA, Vol. 141 http://jada.ada.org January 2010 47

THE CHALLENGE

A general dentist referred a 69-year-old woman to

an otolaryngologist for evaluation and manage-

ment of multiple painful oral ulcerations that had

been present for seven months. The patient’s

symptoms began with mild but increasing

burning of the oral cavity, which developed into

discrete ulcerations of the tongue and buccalmucosa. The otolaryngologist performed a tongue

biopsy. According to the patient, the biopsy

results were benign and she was treated with sys-

temic antiviral therapy without relief. She was

referred to another otolaryngologist at the quater-

nary care medical center, Medical College of

Georgia, Augusta, where she received prescrip-

tions for both an antifungal and an anesthetic

mouthrinse, with minimal resolution of the

lesions. The otolaryngologist then referred her to

our office for evaluation by one of us (S.S.D.).

The patient’s medical history was significant

for hypertension and severe asthma. She was

treated with antihypertensive medications

including enalapril and furosemide, systemic

prednisone (7.5 milligrams per day) and both cor-

ticosteroid and β-agonist inhalers in combination

with montelukast, a leukotriene inhibitor. She

had been admitted to the hospital several times

because of her asthma, with the most recent hos-

pitalization 18 months before her initial evalu-

ation in our office. The review of systems was sig-nificant only for pulmonary symptoms related to

asthma (that is, shortness of breath, coughing,

wheezing) and her complaint of oral sores.

The clinical examination revealed no cervical

lymphadenopathy, no lesions on exposed skin and

no conjunctival erythema. An oral soft-tissue

examination revealed a 1-centimeter, ovoid, shal-

low ulceration on the left buccal mucosa, areas of

which were surrounded by erythema and white

keratosis. The patient’s tongue was papillated nor-

mally, and an irregularly shaped deep ulceration

with indurated and hyperplastic margins was

located on the middorsum (Figures 1 and 2).

Can you make the diagnosis?

D. malignant neoplasm

E. herpetic viral infection

A. median rhomboid glossitis

B. recurrent aphthous stomatitis

C. deep fungal infection

Figure 1. A large nodular ulceration of the dorsal surface of thetongue.

Figure 2. Large, painful ulceration of the left buccal mucosademonstrating a white, raised and circinate border.

Copyright © 2010 American Dental Association. All rights reserved. Reprinted by permission.




THE DIAGNOSIS

C. Deep fungal infection

Deep fungal infections can be the cause of iso-

lated ulcerative lesions of the oral cavity and

should be considered in patients with known or

suspected immunosuppression.1 Deep fungal

infections can include histoplasmosis, blastomy-

cosis, mucormycosis, aspergillosis, cryptococcosis

and coccidioidomycosis. Histoplasmosis is caused

by the fungus Histoplasma capsulatum, which is

endemic to the Ohio and Mississippi River val-

leys. In the United States, approximately 40 mil-

lion people have been infected with H. capsu-

latum and about 500,000 new cases are reported

each year.2-4 H. capsulatum is found most often inareas contaminated with bird or bat droppings,

such as caves, bird roosts and old houses or

barns, as well as in areas in which the soil is

being disrupted through farming or excavation.

Histoplasmosis results from inhalation of con-

taminated dust of droppings from infected birds;

consequently, the lungs are the primary entry for

this infection. The spectrum of illness ranges from

an asymptomatic infection to severe disseminated

disease, depending on the amount of inoculum

and the patient’s immune status.5 Most immuno-

competent people who develop histoplasmosis are

asymptomatic or have a mild form of the disease.

Patients with symptomatic histoplasmosis have a

flulike syndrome and pulmonary complaints

related to underlying pneumonia or other lung

involvement.6,7 In a small proportion of patients,

histoplasmosis may be widespread (disseminated

histoplasmosis), and it can involve blood,

meninges, adrenal glands and other organs.

Very young or very old people or those who have

underlying immune disorders such as AIDS are

at a higher risk of developing disseminated

histoplasmosis.

People with chronic lung disease (for example,emphysema, bronchiectasis) may be at a higher

risk of developing a more severe infection. Others

at risk include patients receiving corticosteroid

treatment, cytotoxic therapy and treatment with

immunosuppressive agents. Our patient had been

receiving long-term systemic corticosteroid

therapy for management of asthma, but she

denied any known exposure to bird droppings or

an occupational exposure. She was unaware of

any bat infestation in her home.

Oral involvement in histoplasmosis usually is

secondary to pulmonary disease or a manifesta-

tion of disseminated infection.7 Oral lesions can

appear papular, nodular, vegetative or ulcerative.

The oral lesions begin as an area of erythema

that becomes a papule, which eventually forms a

granulomatous-appearing ulcer. Up to 40 to 50

percent of patients with systemic histoplasmosis

have oral ulcerations.6 The major oral sites

affected are the mucosa, tongue, palate, gingiva

and periapical region of the teeth.The diagnosis of histoplasmosis depends on the

suspected location of infection. Tests may include

analysis of the organism in sputum, lung tissue,

blood, cerebrospinal fluid (CSF) or bone marrow

tissue, as well as antigen tests performed on

blood, urine or CSF.1

Histologic evaluation often reveals granuloma-

tous inflammation with small spore-form oval

yeasts within macrophages and reticuloendothe-

lial cells.7 Multinucleated giant cells and histio-

cytes usually are present and are interspersed

among other inflammatory cells. Although spores

can be seen with routine hematoxylin-eosin

staining, they are visualized more easily with

special staining such as periodic acid–Schiff

(PAS) and methenamine silver.7 Our patient’s

biopsy specimen revealed numerous small cir-

cular and ovoid fungal organisms throughout the

submucosa and within the cytoplasm of histio-

cytes and giant cells (Figure 3).

The mainstay of treatment for histoplasmosis

is systemic antifungal therapy. In the case of pul-

monary histoplasmosis, treatment may include

systemic drugs such as itraconazole, voriconazole

or ketoconazole. Immunocompromised patientswith disseminated histoplasmosis often receive

treatment with intravenous amphotericin B.

Immunocompetent patients are treated with itra-

conazole or ketoconazole for six to 12 months. Our

patient was treated with a four-week course of

voriconazole (200 mg orally twice daily) in consul-

tation with an infectious disease specialist, who

ruled out disseminated disease via serologic tests

48 JADA, Vol. 141 http://jada.ada.org January 2010





and bronchoscopy. The patient’s oral lesions had

resolved completely at the one-month follow-up

visit after her four-week course of antifungal

therapy.

One of the challenging aspects of this case was

the multifocal and varied appearance of two dis-

tinct lesions, one on the tongue and the other on

the buccal mucosa. In this patient, the tongueulceration appeared deeper and more nodular

than its counterpart on the buccal mucosa. In

addition to deep fungal infections, the differential

diagnosis can include a variety of granulomatous

disease processes that may exhibit similar clinical

characteristics to those of fungal infections, such

as tuberculosis, syphilis or even a gastrointestinal

process like Crohn disease. Therefore, it is vital

for the clinician to rule out systemic complaints

that may indicate a more widespread process. In

addition, the prudent clinician should inform the

pathologist of his or her clinical impression (dif-

ferential diagnosis) so that the pathologist can

use appropriate special tissue stains on the

specimen to rule out infectious or granulomatous

processes.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis for chronic, multiple

ulcerations of the oral cavity can be extensive and

requires careful history taking, physical exami-

nation, histologic evaluation and occasionally lab-

oratory testing to narrow down the diagnostic

possibilities.


A

C D

B

Figure 3. Oral histoplasmosis histologic findings. A. Ulcerated, well-vascularized stroma containing a diffuse mixed inflammatory infiltrate

composed mainly of large, mononuclear histiocytes with epithelioid or vesicular-shaped nuclei and abundant cytoplasm and neutrophils, aswell as occasional multinucleated giant cells. No discrete granulomas were identified (hematoxylin-eosin stain, ×40). B. Numerous organismscan be seen (arrows) amid the mononuclear histiocytes (hematoxylin-eosin stain, ×400). C. Periodic acid–Schiff stain highlights the organismsin magenta (arrows). D. Gomori methenamine silver stained the organisms black.





Median rhomboid glossitis. Median rhom-

boid glossitis (MRG) is an often asymptomatic

erythematous patch of atrophic mucosa on the

dorsal surface of the tongue secondary to chronic

candidal infection.1,8

Historically, researchers con-sidered MRG to be a developmental defect, and it

rarely was treated. The lesion often begins as a

narrow patch of redness on the medial fissure of

the dorsal surface of the tongue. It usually is

asymptomatic and enlarges gradually. Over time,

if untreated, the lesion can exhibit the erythema-

tous nodular hyperplasia characteristic of chronic

hyperplastic candidiasis.8

The diagnosis of MRG requires proper identifi-

cation of candidal organisms, which is accom-

plished most easily via microscopic examination

of cytologic scrapings with PAS staining, Gram

staining or potassium hydroxide preparation. Although carcinoma of the dorsal surface of the

tongue is rare, clinicians also should consider per-

forming a biopsy if there is any clinical suspicion

of malignancy. Treatment of patients with MRG

may involve long-term topical antifungal therapy

along with management of any predisposing fac-

tors, such as xerostomia.

Recurrent aphthous stomatitis. Recurrent

aphthous stomatitis (RAS) is the most common

cause of ulcers in the oral cavity, affecting

approximately 20 percent of the population.

Although the etiology remains to be elucidated,

investigators have proposed several local, sys-

temic, immunologic, genetic, allergic, nutritional

and microbial factors.9 RAS usually affects adoles-

cents and young adults, but it can be seen in older

patients as well. Trauma often is a causative

factor in the development of aphthae in suscep-

tible people via disruption of the mucosal surface

barrier and induction of inflammation.9

The classic lesions of RAS are acute and recur-

ring single or multiple ulcerations associated with

prodromal burning before the ulcer appears.

These round, painful ulcers are covered by a

yellowish gray fibrinous pseudomembrane andare surrounded by an erythematous halo on less

heavily keratinized or movable mucosa.1

The three clinical categories of RAS are minor,

major and herpetiform. Minor aphthae account for

more than 80 percent of all aphthae cases; the

lesions generally are smaller than 1 cm in diam-

eter, last 10 to 14 days and heal without scarring.

Major aphthae are larger, more numerous and

longer lasting and they often heal with residual

scarring. Herpetiform aphthae usually consist of

numerous small ulcerations that appear in crops

and may develop on any oral mucosal surface.

Treatment of RAS ranges from topical emollients,topical corticosteroids and intralesional steroid

injections to systemic medications such as pentoxi-

fylline, colchicine or thalidomide for severe disease.1

Malignant neoplasm. Clinicians must con-

sider malignant neoplasm in the differential diag-

nosis of persistent, nonhealing oral ulceration. In

most cases, the cancer manifests as a solitary

lesion; squamous cell carcinoma is the most fre-

quent diagnosis. In cases in which multiple or

multifocal ulcerations are present, clinicians less

commonly include malignancy in the differential

diagnosis. Nonetheless, they can consider cancers

such as leukemia and metastatic tumors. Leu-kemias, typically of myeloid lineages, can mani-

fest as oral ulceration, often with concomitant

gingival swelling or enlargement.10 Soft tissues,

including the gingiva and tongue, are the most

common sites of involvement. In the case of

metastatic disease, the gingival tissues are

affected most frequently; multifocal presentations

are uncommon but may occur. Treatment of

patients with such conditions requires the

involvement of oncologists and usually involves

some form of chemotherapy.

Herpetic viral infection. Viral infections can

cause multiple painful ulcerations in the oral

cavity. In light of our patient’s clinical presenta-

tion, a differential diagnosis should include ulcers

secondary to herpes simplex virus or cyto-

megalovirus (CMV). Intraoral recurrent herpes

lesions almost always appear on heavily kera-

tinized tissue in the oral mucosa, which aids the

practitioner in distinguishing them from aphthae.

Clinically, these lesions can appear as shallow, ser-

pentine ulcerations or clusters of ulcerations that

coalesce. In some cases, they may appear similar to

tissue that has undergone local trauma or physical

irritation. An important distinguishing feature isthe presence of a vesicular eruption that precedes

the appearance of the lesions.

In immunocompromised patients, herpes

lesions can develop on any mucosal surface with

often uncharacteristic features that make clinical

diagnosis difficult. Although intraoral herpes

lesions are a self-limited process in immunocom-

petent patients, treatment with systemic antiviral

50 JADA, Vol. 141 http://jada.ada.org January 2010





medications such as acyclovir, valacyclovir or fam-

ciclovir is effective if initiated within the first 48

to 72 hours of vesicular formation and eruption.

However, in many cases, the condition is diag-

nosed too late for systemic antiviral therapy to beeffective, but supportive measures, including anal-

gesics and hydration, are important.

CMV is a member of the herpes family of

viruses and occurs worldwide. Most people

infected with CMV have subclinical infections. In

fact, clinical oral manifestations of CMV rarely

are encountered. However, in immunocompro-

mised patients, CMV can cause salivary gland

disease and ulcerations in the oral cavity.

Immunocompromised patients often require

aggressive treatment with intravenous ganci-

clovir, foscarnet or cidofovir.

CONCLUSION

Patients receiving long-term treatment with

immunosuppressant medications are at risk of

developing a multitude of processes that can

cause chronic oral ulcerations. Clinicians should

include infectious processes of viral, bacterial and

fungal etiologies, as well as malignant processes,

in the differential diagnosis. Timely and accurate

diagnosis via thorough history taking and proper

diagnostic techniques, including biopsy, are of

utmost importance. ■

Dr. DeRossi is the chairman, Department of Oral Health and Diag-nostic Sciences, and an associate professor of oral medicine, MedicalCollege of Georgia School of Dentistry, 1120 15th St., Augusta, Ga.30912-1241, e-mail “[email protected]”. Address reprint requests toDr. DeRossi.

Dr. Ciarrocca is an instructor, Department of Oral Rehabilitation andDepartment of Oral Health and Diagnostic Sciences, Medical College of Georgia School of Dentistry, Augusta.

Dr. Alawi is an assistant professor, Department of Pathology, Schoolof Dental Medicine, University of Pennsylvania, Philadelphia.

Disclosure. None of the authors reported any disclosures.

Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine.

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3. Narayana N, Gifford R, Giannini P, Casey J. Oral histoplasmosis:an unusual presentation. Head Neck 2009;31(2):274-277.

4. Psevdos G Jr, Tanowitz HB. Oral histoplasmosis. AIDS Read2008;18(4):217-218.5. Alcure ML, Di Hipólito Júnior O, Almeida OP, Bonilha H, Lopes

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6. Rahman MT, Bakar NH, Philip R, Shamsudin AR. Oral histoplas-mosis presenting as oral ulcer in a non-HIV patient. Southeast Asian JTrop Med Public Health 2004;35(2):388-390.

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Oral Ulcer at Ions in a Patient With Severe Asthma