Histoplasmosis of the larynx

Histoplasmosisof the Larynx ROBERT THAYER SATALOFF, MD, DMA, ANNE WILBORN, MD, ANTHONY PRESTIPINO, MD, MARY HAWKSHAW, RN, BSN, REINHARDT J. HEUER, PHD, AND JOHN COHN, MD Introduction: Laryngeal

histoplasmosis was first described in 1952. Since then, fewer than 100 cases had been reported. This dimorphic fungus is endemic in the Mississippi and Ohio River Valleys. The yeast phase is responsible for human infection. Methods: We report a 44-year-old woman who developed laryngitis. The markedly abnormal larynx, which could have been mistaken for papillomatosis, was biopsied, at which time the diagnosis of histoplasmosis was confirmed. Treatment with oral ketoconazole was instituted. Results: Objective voice assessment showed abnormalities of maximum phonation time, speaking fundamental frequency, perturbation, percent voicing, mean flow rate, and spectral pattern. Subsequent to antifungal therapy, objective measures were improved. Conclusion: This represents the first case of laryngeal histoplasmosis in which response to therapy is documented by objective vocal assessment, Copyright 0 1993 by W.B. Saunders Company

Histoplasmosis of the larynx is an uncommon disease that may cause prolonged hoarseness. Laryngeal symptoms and signs may suggest malignancy. Accurate diagnosis and nonsurgical treatment can produce resolution of the lesion and return of good voice. CASE REPORT A 44-year-old woman developed laryngitis in February 1988. She did not smoke or abuse her voice, and she had no pressing professional or avocational vocal pressures. She was examined by another otolaryngologist in May 1988, at which time a unilateral vocal polyp was diagnosed. Speech therapy was recommended but declined. She was treated with numerous inhalers, steroids, antibiotics, and decongestants. Her hoarseness persisted, and she underwent bilateral vocal fold “stripping” in August 1988. Histopathological examination without special stains showed chronic laryngitis. Attempts were made to obtain the original biopsy material, but neither the slides nor the

From the Department of Medicine, Thomas Jefferson University, the Department of Pathology, Graduate Hospital, and the American Institute for Voice and Ear Research, Philadelphia, PA; and the Columbia Presbyterian Medical Center, New York, NY. Address reprint requests to Robert Thayer Sataloff, MD, DMA, Professor of Otolaryngology, Thomas Jefferson University, 1721 Pine St, Philadelphia, PA 19103. Copyright 0 1993 by W.B. Saunders Company 0196-0709/93/l 403-0009$5.00/O American

Journal

of Otolaryngology,

block could be found. Consequently, we do not know whether histoplasmosis was missed originally or whether the infection was acquired following her first operation. Hoarseness and vocal fold irregularities persisted, and she was referred to the author (R.T.S.) in November 1988. Examination showed marked hoarseness, and severe functional dysphonia with whispered voice. The functional dysphonia was overcome through intensive voice therapy, including relaxation techniques, stress management, voice facilitation through coughing and laughing, and other techniques. After the functional component had been overcome, strobovideolaryngoscopy showed bilateral vocal fold masses, an anterior web, and markedly hypodynamic (but not adynamic) motion bilaterally. The vocal fold masses were erythematous, bulky, moderately irregular, and asymmetric, but they were covered with mucosa. They could easily have been mistaken for papillomas (Fig 1). She was followed closely, and no improvement was noted following 8 weeks of voice therapy. Surgery was recommended. A suspension microlaryngoscopy with discrete excision of both vocal fold masses was performed. Histoplasmosis was diagnosed (Figs 2, 3 and 4). She developed a large left vocal fold inclusion cyst that was resected in May 1989. In the interim, as soon as histoplasmosis was diagnosed, she was referred for complete medical evaluation, including computed tomography (CT), lumbar puncture, chest roentgenogram, hepatic ultrasound, bone marrow examination, extensive laboratory studies, and other tests. This workup showed no evidence of disseminated disease. She was treated with oral ketoconazole, 200 mg three times daily, for 3 months. Before surgery in March 1989, objective voice assessment showed signifi-

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Pig 1.

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Preoperative

appearance

of the vocal fold masses.

cant abnormalities of maximum phonation time, speaking fundamental frequency, perturbation, percent voicing, s/zratio, mean flow rate (Table l), and spectral pattern (Fig 5). The test results and her vocal quality did not improve initially following surgery. However, her voice began to improve toward the end of her antifungal therapy. Despite the web, her voice improved dramatically. She reported that it sounded “normal” to her. Objective measures were improved, although not within normal limits (Table 1; Fig 6), approximately 14 months following completion of antifungal therapy. DISCUSSION Histoplasmosis, a disease with variable manifestations, is caused by the dimorphic fungus Histoplasma capsulatum. This fungus, which is endemic in the Mississippi and Ohio River valleys, exists in both a mycelial and a yeast phase. The yeast phase is responsible for human infection. Although the mycelial phase exists at room temperature, when inhaled, the increased temperature of the body allows the yeast phase to predominate and invade the reticuloendothelial system. This leads to pulmonary infection and hematogenous spread, which is often clinically insignificant. Rarely,

ET AL

chronic dissemination occurs, and it is this form of histoplasmosis that most often leads to laryngeal manifestations. Infection with H capsulatum is relatively common, particularly in endemic areas, where up to 85% of sampled populations have positive skin tests.’ However, dissemination is quite rare as a clinically apparent infection.’ This scenario is more likely to occur in the immunocompromised or elderly patient and is more common in men. When disseminated disease occurs, histoplasma can infect almost any organ. Areas commonly involved include bone marrow, lymph nodes, adrenal glands, and the gastrointestinal (GI) tract,3-” as well as laryngeal, tongue, and buccal mucosa. Nonspecific symptoms include fever, weight loss, and general malaise.5 When disseminated disease is present, oropharyngeal and laryngeal occurrence is surprisingly frequent. Goodwin et al found that 66% of those with chronic disseminated disease demonstrated oropharyngeal ulcers, and 24% had laryngeal lesionss3 Smith and Utz, in a prospective study in 1972, demonstrated that only 15% of patients studied manifested isolated laryngeal disease, but 42% manifested orolaryngeal disease.5 Symptoms of laryngeal infection include sore throat, hoarseness, cough, dysphagia, and occasionally stridor.7-12 On visualization, the laryngeal mucosa may appear pearly white and edematous or inflamed and ulcerative. Lesions may resemble carcinoma or tuberculosis.13 Biopsy will show granulomatous tissue, often containing necrosis, with an infiltrate of giant cells, lymphocytes, plasma cells, and large numbers of macrophages. A high index of suspicion for histoplasmosis must be maintained, as the organism is not easily demonstrable on hematoxylin and eosin stain. However, with Gomori methenamine silver stain, macrophages will be noted to contain variable numbers of round or oval bodies surrounded by a clear zone. These bodies are the intracellular yeast forms of H. capsulatum. Many cases of laryngeal histoplasmosis have been described, the first occurring in 1940 as reported by Brown, Havens, and Magathe7 The literature describes numerous instances in which laryngeal symptoms led to

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Fig 2. Laryngeal biopsy shows granuiomatour inflammation with epithsliai histiocytes and muttinucieated giant ceils. Oval organisms surrounded by an lrtlfllctuai clear zone are evident within a multinucleated giant ceil Unset].

pas, and EricksonzO described a similar case in the diagnosis of histoplasmosis,1~2~7~1z~14~zgofwhich no evidence of dissemination could be ten before other signs of dissemination had found. occurred. Although most authors agree that laIn order to definitively diagnose histoplasryngeal manifestations are indicative of dismosis, organisms must be identified on biopsy seminated disease,2-4*1g~30cases have been reor culture, but tests such as the histoplasmin ported in which the laryngeal lesion was believed to be primary (Table 2).8,10,11,14~16,18,20,25 skin test and complement fixation can be useful. Although skin testing is often unreliable, In 1950, Roberts and Forman first described complement fixation appears to be the most two cases of laryngeal histoplasmosis.14 specific serologic method of diagnosis.24 TiHutchinson” described a case in which disease was apparently not only limited to the ters can be followed during therapy to deterlarynx but more specifically to the right vocal mine the adequacy of treatment. A successful culture may be aided by obtaining the tissue fold. Eleven years later, in 1963, Withers, Pap-

Fig 3. Periodic acid-Schiff stain demonstrates intracellular yeast forms mearuring approximately 3 to 5 pm, consistent with H capsulatum.

SATALOFF ET AL

Fig 4. Pseudoepitheliomstous hyperplasia of squamous apithalium is obsarvad overlying granulomatous inflammation.

for culture at the time of laryngoscopy if the diagnosis is suspected preoperatively. For many years, drug therapy was unsuccessful in eradicating histoplasmosis infection. Despite numerous medications, patients would often die of disseminated disease. However, if administered in sufficient amounts, amphotericin B will cure patients of this disease. Goodwin et al3 attempted to maintain a blood level of 1.56 mg/mL for 10 weeks, stating that a total of 1 g of intravenous amphotericin B usually delivers adequate treatment. Amphotericin B has many side effects, the most notable of which is severe renal toxicity. Blood urea nitrogen and creatinine levels must be monitored. In light of the serious side effects of amphotericin B, other medications have been tried. Ketoconazole31*32 and itraconazole33 have both been used to treat laryngeal histoplasmosis with promising results. TABLE1.

CONCLUSION Since 1952, when laryngeal histoplasmosis was first described in the literature, less than 100 cases have been reported.31,33-43 These numbers are quite small in comparison with the number of patients diagnosed as having histoplasmosis each year. Nevertheless, the laryngologist must be familiar with this entity. It should certainly be considered as a cause of hoarseness in any patient known to have systemic histoplasmosis. In addition, it should be included in the differential diagnosis of vocal fold masses producing hoarseness. Diagnosis generally requires biopsy, especially if proven disseminated disease is absent. When suspected preoperatively, biopsy should be limited, removing as little tissue as needed to establish a diagnosis. The pathologist should be alerted to the need for special stains. Tissue for culture is also helpful. Extensive workup

Objective Voice Measures

Maximum phonation time (seconds) Physiologic frequency range Speaking fundamental frequency (Hz) Jitter s/z Ratio Mean flow rate (mL/s) Shimmer

Pretreatment

Posttreatment

Normal Data

7.61 Unmeasurable 243-313 6.9 2.36 100.93 -

16.58 16 semitones 202 4.35 0.56 66.56 .75

25.7 35 semitones 220 0.46 1 92 0.57

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LARYNX

1 KHz_

C

-b

A

5Kl-k 3KHz

Fig 5. (AI Pretreatment narrow band spectrography has three observable harmonics (a, b, cl. The (FO) (a) is strong. The first harmonic (b) is weak and intermittent. The third harmonic fc) is stronger. Harmonics in the rangebetween3kHzand4kHr are very disrupted. There is a noise component between 6 kHz and 8 kHz. (B) Pretreatment wide-band spectrography also demonstrates high levels of noise. The fundamental (a) and first two formants fb and cl are identifiable and demonstrate intermittency. Energy is observable in the area of the third formant (a) but is extremely intermittent. These sonograms are representative of a high-pitched (250 Hz FO), weak, hoarse voice.

.”

1 I

i

Fig 6. (A) Posttreatment narrow-band spectrogram shows harmonic structure throughout

strong first and second formants (a, b) and observable third and fourth formants fc, d). The third and fourth formnnts are somewhat disrupted by noise. This sonogram is cheracteristic of a somewhat low-pitched (181 Hz) female voice with a mild degree

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TABLE2.

SATALOFF ET AL

Summary of Reported Cases

Histoplasmosis Limited to Larynx Two cases reported Anterior RVF Ulceration both VF Solitary lesion LVF Larynx and epiglottis Larynx Abbreviations:

Author

Year

Site

Appearance

Roberts and Forman Hutchinson Withers et al Kuilman and Bakker Hoffarth et al Sataloff et al

1950 1952 1963 1970 1973 1991

L and R VF RVF L and R VF LVF Larynx L and R VF

Granulomatous Granulomatous Mucosa appeared white Hyperemia swelling Exophytic lesions Exophytic lesions

L, left; R, right; VF, vocal fold.

to rule out disseminated disease is recommended. Treatment requires antifungal medication. REFERENCES 1. Calcaterra TC: Orolaryngeal histoplasmosis. Laryn_ goscope 80:111-120,197O 2. Hoffarth GA, Joseph DL, Shumrick DA: Deep mycases. Arch Otolaryngol Head Neck Surg 97:475-479, 1973 3. Goodwin RA, Shapiro JL, Thurman GH, et al: Disseminated histoulasmosis: Clinical and pathological correlations. Medic&e 59:1-33, 1980 4. Bennett DE: Histoplasmosis of the oral cavity and larynx. Arch Intern Med X.0:417-427, 1967 5. Smith JW, Utz JP: Progressive disseminated histoplasmosis: A prospective study of 26 patients. Ann Intern Med 75:557-565, 1972 6. Lierle DM, Carr TL: Histoplasmosis in the adult: Case report and review of the literature. Laryngoscope 61:230-237, 1961 7. Brown AC, Havens FZ, Magath TB: Histoplasmosis: Report of case. Proc Staff Meet Mayo Clinic, 15:812-816, 1940 8. Dean LW: Histoplasmosis of the larynx. Arch Otolaryngol Head Neck Surg 36:390-392, 1942 9. Palmer AE, Amolsch AL, Shaffer LW: Histoplasmosis with mucocutaneous manifestations. Arch Dermatol 45:912-916, 1942 10. Van Pernis PA, Benson ME, Holinger PH: Case reports: Laryngeal and systemic histoplasmosis (Darling). Ann Intern Med 18:384-393, 1943 11. Parkes M, Burtoff S: Histoplasmosis of the larynx: Report of a case. Med Ann DC l&641-643,1949 12. Gammell EB. Breckenridae RL: Histoplasmosis of the larvnx. Ann O&l Rhin Larykgol 58:249-i59, 1949 13. &hlech WF, Carden GA: Fungal and parasitic granulomas of the head and neck. Otolarvngol _ _ Clin North Am 15:493-513, 1982 14. Roberts SE, Forman FS: Histoplasmosis-A deficiency disease: Report of two cases with laryngeal involvement. Ann Otol Rhino1 Laryngol 59:809-822, 1950 15. Hulse WF: Laryngeal histoplasmosis. Arch Otolaryngol Head Neck Surg 54:65-67, 1951 16. Hutchinson HE: Laryngeal histoplasmosis simulating carcinoma. J Path Bact 64:309-319, 1952 17. Zinneman HI-I, Hall WH: Chronic pharyngeal and laryngeal histoplasmosis successfully treated with ethyl vanillate. Minn Med 36:249-252, 1953 18. Burton CT, Wallenborn PA: Histoplasmosis of the larynx. Va Med Month 80:665-868,1953

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