Vol. 117 No. 3 March 2014

A nonhealing ulcer of mandibular alveolar ridgeVirendra Singh, MDS,a Pranav Gupta,a Shruti Khatana,a Amrish Bhagol, MDS,a and Ambika Gupta, MDSb

Government Dental College, Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India

(Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:272-276)

CASE PRESENTATIONA 60-year-old man presented to the oral and maxillofacial

surgery clinic at the Pt. B. D. Sharma Institute of HealthSciences, Rohtak, with a chief complaint of painful ulcerationin the oral cavity for the past 2 months. A private practitionerextracted his mandibular left posterior teeth �3 months pre-viously. According to the patient, the extraction wound didnot heal even after 3 weeks, and apparently it had been slowlyincreasing in severity during this period. The patient was thenreferred to our oral and maxillofacial surgery clinic.

At the initial examination, the patient presented with anulcerated lesion with indurated rolled margins extending an-teroposteriorly from the left mandibular canine region to thefirst molar region on the crest of the alveolar ridge andlaterally, involving the buccal vestibule along its length (Fig-ure 1). The lesion was painful on palpation and was coveredwith a yellowish pseudomembrane. No cervical lymphade-nopathy was noted. The patient was concerned that the lesionin his mouth might be related to a malignancy.

His medical history revealed that he had poorly controlleddiabetes treated with insulin injection. He had been treated bythe Department of General Medicine with prednisolone (wys-olone) 7.5 mg for �8 months for the treatment of sarcoidosis.The patient did not report dyspnea, cough, nausea, or abnor-mal bowel movements, although he did report a several-month history of evening rise of body temperature, loss ofappetite, increased fatigue, and mild generalized malaise.

Physical examination revealed a thin frail patient with mildhepatosplenomegaly, no associated abdominal tenderness, andno cardiac or respiratory problems. He was seronegative forHIV, HBV, HCV, and tuberculosis.

The laboratory investigations revealed raised angiotensin-converting enzyme (156 U/L), blood glucose levels bothfasting (134 mg/dL) and postprandial (288 mg/dL), and gly-cosylated hemoglobin (8.3%). The complete hemogram andblood biochemistry were within normal ranges. Contrast-enhanced computerized tomography (CECT) for chest andabdomen revealed evidence of mild hepatosplenomegaly, butno evidence of lymphadenopathy. An orthopantomogram re-vealed bone loss in the region of the mandibular left first andsecond premolars.

aDepartment of Oral and Maxillofacial Pathology.bDepartment of Oral Diagnosis and Radiology.Received for publication Jan 3, 2012; returned for revision Jun 9,2012; accepted for publication Jun 15, 2012.© 2014 Published by Elsevier Inc.2212-4403/$ - see front matter

http://dx.doi.org/10.1016/j.oooo.2012.06.016

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DIFFERENTIAL DIAGNOSISThe initial evaluation of this patient involved a detailedhistory and physical examination, along with examinationof appropriate laboratory and radiographic studies. All ofthese data aided in the compilation of the differentialdiagnosis, which included squamous cell carcinoma, We-gener granulomatosis, tuberculosis, oral sarcoidosis, syph-ilis, mucormycosis, and histoplasmosis.

Squamous cell carcinomaSquamous cell carcinoma of the mucosa of the alveolarridge can be a potential diagnosis for this patient aspresented. Carcinoma of the alveolar ridge usuallymanifests as a nonhealing ulcerative lesion of alveolarridge with rolled margins, is usually painless unlesssecondarily infected, and shows destruction of under-lying bone, with defined or irregular margins.1 Lymph-adenopathy is found at later stages of oral disease. Boththe clinical and radiographic presentations in the pres-ent case were consistent with squamous cell carcinoma.

Wegener granulomatosisWegener granulomatosis is a rare chronic disease ofunknown origin, although an immunologic mechanismmay be involved. Pulmonary and renal involvement arethe most common and most severe manifestations ofthe disease. Oral lesions are fairly common, and theymay appear as solitary or multiple ulcers surrounded byan inflammatory zone. Tongue, palate, and buccal mu-cosa are commonly affected and rarely, an early featureof the disease may be a peculiar gingival enlargementwith a rough, red, papillary, and granulomatous surface.Skin lesions occur in half of the patients and are char-acterized by papules, petechiae, plaques, and ulcers.The diagnosis is confirmed by clinical features, radio-graphic features, biopsy, and serum investigation forantineutrophil cytoplasmic antibody (ANCA).2 Thepainful ulcerative lesion of our patient prompted us toinclude this condition in the differential diagnosis;however, the typical clinical presentation was absent inour case. Negative serum investigations for c-ANCAand p-ANCA effectively ruled out the condition.

TuberculosisOral tuberculous lesions may be either primary or sec-

ondary in occurrence. Primary lesions are uncommon,

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seen in younger patients, and present as a single pain-less ulcer with regional lymph node enlargement. Sec-ondary lesions are common, often associated with pul-monary disease, and usually present as a single,indurated, irregular, painful ulcer covered by inflam-matory exudate in patients of any age group, but rela-tively more commonly in middle-aged and elderly pa-tients.3 Oral tuberculosis may occur at any location onthe oral mucous membrane, but the tongue is mostcommonly affected. Oral lesions may present in a va-riety of forms, such as ulcers, nodules, tuberculomas,and periapical granulomas. The typical presentation isthat of a single indurated painful ulcer with irregularborders covered by inflammatory exudates; however,atypical cases with multiple lesions or asymptomaticulcers have also been described.1 The identification ofa tuberculous lesion in any location in the mouth is anunusual finding, and its discovery is usually indicativeof underlying pulmonary disease. In the present patient,an indurated painful ulcer with irregular borders, cov-ered with necrotic slough, pointed toward a tuberculouslesion, but the absence of a primary site of the diseasemade it less likely.

Oral sarcoidosisSarcoidosis is a systemic disease of unknown etiologythat may affect any organ and can cause significantmorbidity and even death. Clinically evident oral man-ifestations in sarcoidosis are uncommon, if salivarygland and lymph node involvement are excluded. Themost frequently affected intraoral site is the buccalmucosa, followed by gingiva, lips, floor of mouth,tongue, and palate. If oral lesions are present, theymanifest as a submucosal mass, an isolated papule, an

Fig. 1. Clinical photograph of the patient, showing the ulcer-ative lesion of left mandibular alveolar ridge. There wasattempted surgical exploration by a private practitioner, asindicated by a suture at the anterior margin of the lesion.

area of granularity, or an ulceration. The diagnosis is

established by the clinical and radiographic presenta-tions, histologic features, and the presence of negativefindings with both special stains and cultures for organ-isms. Elevated angiotensin-converting enzyme levelsand appropriate documentation of pulmonary involve-ment strongly support the diagnosis.4 Because our pa-tient had a diagnosed case of systemic sarcoidosis,there was high suspicion that the oral lesion representedan oral manifestation of oral sarcoidosis.

SyphilisSyphilis is a worldwide chronic infection produced bythe bacterium Treponema pallidum. The oral lesion inprimary syphilis presents as a painless clean-based ul-cer (chancre) or, rarely, as a vascular proliferationresembling a pyogenic granuloma, more commonlyoccurring on the lips. The clinical features and locationmake primary syphilis unlikely in our patient. In sec-ondary syphilis, red maculopapular areas may be foundorally, with subsequent superficial epithelial necrosisleading to sloughing and exposure of underlying con-nective tissue. However, this is also associated withsystemic symptoms such as malaise, painless lymph-adenopathy, sore throat, headache, weight loss, andmusculoskeletal pain.4 These features were not noted inour patient. The tertiary stage, with oral gumma forma-tion and possible perforation into the nasal cavity,along with other systemic problems, was considered tobe less likely in our patient.

Mucormycosis (zygomycosis)Mucormycosis is an opportunistic, frequently fulmi-nant, fungal infection that is caused by normally sap-rophytic organisms of class Zygomycetes. Rhinocere-bral mucormycosis is the most common form, and ittypically involves the nose and sinuses.5 If the maxil-lary sinus is involved, the initial presentation may beseen as intraoral swelling of the maxillary alveolarprocess, the palate, or both. Massive tissue destructionmay result if the condition is not treated. Radiograph-ically, opacification of maxillary sinuses may be ob-served in conjugation with patchy effacement of thebony wall of the sinuses. The immune-compromisedstate of our patient due to long-term steroids and dia-betes may have predisposed him to mucormycosis.However, the site of lesion makes it less likely, becausemandibular involvement is rare.

HistoplasmosisHistoplasmosis, the most common systemic fungal in-fection in the USA but rare in India, is caused by theorganism Histoplasma capsulatum. Histoplasmosis isclinically classified as a primary acute pulmonary form

that is usually asymptomatic, a chronic pulmonary form

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that occurs in the presence of underlying pulmonarydisease, or a disseminated form, which occurs almostexclusively in infants, the elderly, and in debilitated orimmunocompromised patients. The disseminated formis characterized by the progressive spread of infectionto extrapulmonary sites, including the oral cavity or theintestine.6,7 Oral lesions frequently are granulomatousand appear as nodular ulcerative or vegetative lesionsthat may be painful. They may be present anywhere onthe oral mucosa, tongue, hard and/or soft palate, or lips.The ulcers have raised and rolled borders and arecommonly covered by a yellow or grayish pseu-domembrane resembling carcinoma or tuberculosis.8

Definitive diagnosis is usually made by a combina-tion of culture, detection of the organism in tissues,measurement of antibodies, and detection of anti-gen.9 Considering the immune status and medicalhistory of the patient, the clinical presentation of thepresent case was consistent with the localized formof oral histoplasmosis.

The immunocompromised state of the patient, alongwith the clinical presentation of the lesion, raised oursuspicion toward oral sarcoidosis, mucormycosis, andhistoplasmosis. With the additional concern of the pa-tient about malignancy, a confirmatory incisional bi-opsy was planned.

SUBSEQUENT COURSE AND MANAGEMENTAn incisional biopsy was obtained from the lesion onthe alveolar ridge under local anesthesia. The tissuespecimen was submitted for histologic examination.

The histologic examination revealed ulceration ofthe mucosa with a florid inflammatory infiltrate in thesubmucosa. The inflammation comprised sheets of his-tiocytes admixed with lymphocytes, polymorphs, andeosinophils. Scattered ill-defined granulomas com-posed of histiocyes and giant cells were seen (Figure 2).Many of the histiocytes and giant cells contained nu-merous fungal organisms in the cytoplasm, which weresmall and round with a clear halo. Pseudohyphae werealso observed. These intracytoplasmic bodies were bet-ter visualized with Gomori–methenamine silver (GMS)staining (Figure 3). The final diagnosis was fungalgranulomatous inflammation consistent with histoplas-mosis.

After clinical, radiologic, laboratory, and histopatho-logic assessment, treatment was instituted with 200 mgoral itraconazole once a day and clotrimazole (Candidamouthpaint) for topical application. The patient wascontinued on 7.5 mg oral prednisolone (wysolone) oncea day and 1 g metformin twice a day as advised by thepatient’s physician. After 1 week of treatment, theresults were encouraging, because there was significant

symptomatic improvement, and the lesion started re-

gressing in size. The patient continued on the samemedications and kept on periodic observation. The pa-tient was asymptomatic at the latest follow-up of 3months (Figure 4).

DISCUSSIONHistoplasmosis is a systemic mycosis caused by His-toplasma capsulatum, a saprophytic and dimorphicfungus found globally in soil.10 At ambient temper-ature in the soil, it presents as a mycelial form,characterized by septate hyphae that produce micro-conidia. Human contamination occurs by inhalationof the airborne spores, which are phagocyized bypulmonary macrophages and reside within a mem-

Fig. 2. Hematoxylin-eosin stain of a biopsy of the left pos-terior mandible, depicting the granulomatous inflammation(�100).

Fig. 3. Grocott–Gomori methenamine silver stain shows typ-ical yeast cells, some of which were undergoing replicationby budding (�100). The background of this figure appearsblue because of the unavailability of light green stain (counterstain) in the pathology laboratory, methylene blue was used asa counterstain in this case.

brane-bound vacuole. At body temperature, Histo-

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plasma capsulatum converts to the yeast form and isable to replicate in the host.11 Immunocompetentpersons exposed to a low inoculum develop antigen-specific CD4 T-lymphocyte–mediated cellular im-mune responses, with activation of macrophages, andthe disease is controlled.12 When the cell-mediatedimmunity of the host is impaired, Histoplasma cap-sulatum can produce progressive systemic and po-tentially lethal disease with the spread of the fungithrough the reticuloendothelial system.11 In thesecases, the fungi act as an opportunistic agent.9-11

Oral lesions frequently are granulomatous and ap-pear as nodular ulcerative or vegetative lesions thatmay be painful. The ulcers have raised and rolledborders, commonly covered by a yellow or grayishpseudomembrane resembling carcinoma or tubercu-losis.8 Erosion of the underlying bone can also occur.

The vast majority of cases of oral histoplasmosis areassociated with the disseminated form of the disease.13

The most common oral sites of involvement include thetongue, palate, gingiva, and buccal mucosa.14

The laboratory methods available for histoplasmosisdiagnosis include biopsy and culture of tissue, bodyfluids, and secretions, as well as tests for antigens andserum antibodies. Biopsy is indicated mainly for mu-cocutaneous lesions, and special stains such as periodicacid–Schiff and Gomori–Grocott methenamine silverare very useful.9,15-18

The disseminated form of histoplasmosis is typi-cally seen in patients presenting with oral manifes-tations and is usually seen only in immunocompro-mised patients, either secondary to AIDS (especiallywith CD4 counts of �150 cells/mL), immunosup-pressive therapy, or severe debilitation/advancedage. Our patient tested negative for HIV but reportedbeing on oral corticosteroid therapy for a period of�8 months, which was most probably the reason for

Fig. 4. Three-month follow-up photograph, showing com-plete resolution of the lesion with a healthy alveolar ridge.

his immunocompromised state.

Oral histoplasmosis is usually diagnosed after thediscovery of lesions of the upper aerodigestive tractin the absence of pulmonary signs. These lesionsmay remain the only location for a long period,19 andcan be misinterpreted as aphthous and/or traumaticulcers, ulcerative necrotic gingivitis or stomatitis,other mycoses, squamous cell carcinoma, or lympho-mas.3,9,20 The oral lesions are initially budding orwart-like and then develop into ulcerating, indurated,and painful lesions.19 They result from hematoge-nous spread from an unknown infectious focus, al-though some investigators have suggested that, whenno systemic sign or symptom can be detected, oralhistoplasmosis should be considered as a localizeddisease and treated as such.21

In the present patient, because there were no acutepulmonary features, we considered it to be localized oralhistoplasmosis. The histopathologic features were alsoconsistent with chronic granulomatous lesions, and GMSstaining confirmed our diagnosis of histoplasmosis.

The treatment varies according to severity of thedisease and immune status of the host. The dosage anddrug combinations as well as suppressive maintenancetherapy to prevent relapse are variable and must bedetermined for each case.22-24

The recommended therapy for mild to moderatelysevere disseminated histoplasmosis is 200 mg oral itra-conazole twice daily for 6-18 months, the ultimateduration of therapy depending on response to therapyand underlying host resistance.25 In cases of severedisseminated histoplasmosis, an initial short coursewith amphotericin B, switching to itraconazole as thepatient’s condition improves, has been suggested.Long-term prophylaxis with 200 mg itraconazole dailyshould be considered in AIDS patients with CD4 countsof �150-200 cells/mL. Because our patient respondedwell to 200 mg itraconazole twice daily, and the lesionregressed markedly within a period of 2 weeks, he wascontinued on the same regime.

In conclusion, although oral lesions of histoplasmosisisare more common in HIV-infected patients, histoplasmo-sis may also affect persons immunocompromised due toother systemic conditions and medications. Therefore,early diagnosis is important for decreasing the morbidityand mortality of these patients.

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Reprint requests:

Dr. Virendra SinghProfessor and HeadDepartment of Oral and Maxillofacial SurgeryGovernment Dental CollegePt. B. D. Sharma University of Health SciencesRohtak-124001, Haryana

drvirendrasingh1@yahoo.co.in