Oral ulcerations in a patient with severe asthma Scott S. DeRossi, Katharine N.

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CLINICAL PRACTICE

DIAGNOSTIC CHALLENGE

Oral ulcerations in a patient with severe asthma

Scott S. DeRossi, DMD; Katharine N. Ciarrocca, DMD, MSEd; Faizan Alawi, DDS THE CHALLENGE

A general dentist referred a 69-year-old woman to an otolaryngologist for evaluation and management of multiple painful oral ulcerations that had been present for seven months. The patients symptoms began with mild but increasing burning of the oral cavity, which developed into discrete ulcerations of the tongue and buccal mucosa. The otolaryngologist performed a tongue biopsy. According to the patient, the biopsy results were benign and she was treated with systemic antiviral therapy without relief. She was referred to another otolaryngologist at the quaternary care medical center, Medical College of Georgia, Augusta, where she received prescriptions 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 patients 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 corticosteroid and -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 hospitalization 18 months before her initial evaluation in our office. The review of systems was significant 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, shallow ulceration on the left buccal mucosa, areas of which were surrounded by erythema and white keratosis. The patients tongue was papillated normally, and an irregularly shaped deep ulceration with indurated and hyperplastic margins was located on the middorsum (Figures 1 and 2).

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

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

Can you make the diagnosis? A. median rhomboid glossitis B. recurrent aphthous stomatitis C. deep fungal infection D. malignant neoplasm E. herpetic viral infection

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THE DIAGNOSIS

C. Deep fungal infection

Deep fungal infections can be the cause of isolated ulcerative lesions of the oral cavity and should be considered in patients with known or suspected immunosuppression.1 Deep fungal infections can include histoplasmosis, blastomycosis, mucormycosis, aspergillosis, cryptococcosis and coccidioidomycosis. Histoplasmosis is caused by the fungus Histoplasma capsulatum, which is endemic to the Ohio and Mississippi River valleys. In the United States, approximately 40 million people have been infected with H. capsulatum and about 500,000 new cases are reported each year.2-4 H. capsulatum is found most often in areas 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 contaminated 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 patients immune status.5 Most immunocompetent 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 manifestation 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 granulomatous inflammation with small spore-form oval yeasts within macrophages and reticuloendothelial cells.7 Multinucleated giant cells and histiocytes 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 acidSchiff (PAS) and methenamine silver.7 Our patients biopsy specimen revealed numerous small circular and ovoid fungal organisms throughout the submucosa and within the cytoplasm of histiocytes and giant cells (Figure 3). The mainstay of treatment for histoplasmosis is systemic antifungal therapy. In the case of pulmonary histoplasmosis, treatment may include systemic drugs such as itraconazole, voriconazole or ketoconazole. Immunocompromised patients with disseminated histoplasmosis often receive treatment with intravenous amphotericin B. Immunocompetent patients are treated with itraconazole or ketoconazole for six to 12 months. Our patient was treated with a four-week course of voriconazole (200 mg orally twice daily) in consultation with an infectious disease specialist, who ruled out disseminated disease via serologic tests

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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, as well as occasional multinucleated giant cells. No discrete granulomas were identified (hematoxylin-eosin stain, 40). B. Numerous organisms can be seen (arrows) amid the mononuclear histiocytes (hematoxylin-eosin stain, 400). C. Periodic acidSchiff stain highlights the organisms in magenta (arrows). D. Gomori methenamine silver stained the organisms black.

and bronchoscopy. The patients 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 distinct lesions, one on the tongue and the other on the buccal mucosa. In this patient, the tongue ulceration 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 (differential 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 examination, histologic evaluation and occasionally laboratory testing to narrow down the diagnostic possibilities.

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CLINICAL PRACTICE DIAGNOSTIC CHALLENGE

Median rhomboid glossitis. Median rhomboid 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 considered 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 erythematous nodular hyperplasia characteristic of chronic hyperplastic candidiasis.8 The diagnosis of MRG requires proper identification of candidal organisms, which is accomplished 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 performing 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 factors, 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, systemic, immunologic, genetic, allergic, nutritional and microbial factors.9 RAS usually affects adolescents 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 susceptible people via disruption of the mucosal surface barrier and induction of inflammation.9 The classic lesions of RAS are acute and recurring single or multiple ulcerations associated with prodromal burning before the ulcer appears. These round, painful ulcers are covered by a yellowish gray fibrinous pseudomembrane and are 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 diameter, 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 pentoxifylline, colchicine or thalidomide for severe disease.1 Malignant neoplasm. Clinicians must consider malignant neoplasm in the differential diagnosis of persistent, nonhealing oral ulceration. In most cases, the cancer manifests as a solitary lesion; squamous cell carcinoma is the most frequent 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. Leukemias, typically of myeloid lineages, can manifest 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 patients clinical presentation, a differential diagnosis should include ulcers secondary to herpes simplex virus or cytomegalovirus (CMV). Intraoral recurrent herpes lesions almost always appear on heavily keratinized tissue in the oral mucosa, which aids the practitioner in distinguishing them from aphthae. Clinically, these lesions can appear as shallow, serpentine 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 is the 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 immunocompetent patients, treatment with systemic antiviral

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CLINICAL PRACTICE DIAGNOSTIC CHALLENGE

medications such as acyclovir, valacyclovir or famciclovir is effective if initiated within the first 48 to 72 hours of vesicular formation and eruption. However, in many cases, the condition is diagnosed too late for systemic antiviral therapy to be effective, but supportive measures, including analgesics 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 immunocompromised patients, CMV can cause salivary gland disease and ulcerations in the oral cavity. Immunocompromised patients often require aggressive treatment with intravenous ganciclovir, foscarnet or cidofovir.
CONCLUSION

Dr. DeRossi is the chairman, Department of Oral Health and Diagnostic Sciences, and an associate professor of oral medicine, Medical College of Georgia School of Dentistry, 1120 15th St., Augusta, Ga. 30912-1241, e-mail sderossi@mcg.edu. Address reprint requests to Dr. DeRossi. Dr. Ciarrocca is an instructor, Department of Oral Rehabilitation and Department of Oral Health and Diagnostic Sciences, Medical College of Georgia School of Dentistry, Augusta. Dr. Alawi is an assistant professor, Department of Pathology, School of 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. 1. Greenberg MS, Glick M, Ship JA, eds. Burkets Oral Medicine. 11th ed. Hamilton, Ontario, Canada: BC Decker; 2008. 2. Kurowski R, Ostapchuk M. Overview of histoplasmosis. Am Fam Physician 2002;66(12):2247-2252. 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 Read 2008;18(4):217-218. 5. Alcure ML, Di Hiplito Jnior O, Almeida OP, Bonilha H, Lopes MA. Oral histoplasmosis in an HIV-negative patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101(2):e33-e36. 6. Rahman MT, Bakar NH, Philip R, Shamsudin AR. Oral histoplasmosis presenting as oral ulcer in a non-HIV patient. Southeast Asian J Trop Med Public Health 2004;35(2):388-390. 7. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007;20(1):115-132. 8. Whitaker SB, Singh BB. Cause of median rhomboid glossitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81(4):379-380. 9. Scully C. Clinical practice: aphthous ulceration. N Engl J Med 2006;355(2):165-172. 10. Parisi E, Draznin J, Stoopler E, Schuster SJ, Porter D, Sollecito TP. Acute myelogenous leukemia: advances and limitations of treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93(3):257-263.

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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.

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