Cryptococcal infection of the larynx simulating laryngeal carcinoma. (Case Report).

Abstract: Cryptococcus neoformans is an encapsulated yeast that can cause primary pulmonary infections or disseminate and cause infections of the central nervous system, meninges, skin, and bone in the immunocompromised host. We present here an unusual case of an immunocompetent patient who had laryngitis due to C. neoformans that mimicked a laryngeal carcinoma on clinical examination and imaging studies.

**********

Although the causes of hoarseness are numerous, most of them can be divided into three broad categories: inflammatory lesions, benign proliferative lesions, and malignant tumors. (1) A complete history and physical examination including direct visualization of the larynx can often elicit the correct diagnosis, but in many of these cases the diagnosis must be confirmed by tissue sampling and subsequent histopathologic evaluation.

The category of inflammatory lesions can be further subdivided into infectious and noninfectious causes. While the most common cause of laryngitis due to an infectious agent is viral, a number of fungi such as Histoplasma capsulatum and Blastomyces dermatitidis can also cause laryngeal infections. These entities are important to keep in mind during direct visualization of the larynx as they can grossly resemble a malignant process. We describe a nonimmunocompromised patient in whom myotic laryngitis caused by C. neoformans was initially thought to be a malignancy when seen during laryngoscopy.

Case Report

A 60-year-old man was seen because of hoarseness for 4 months. During the initial stages of the illness, he had also had a nonproductive cough that had lasted for only a short time. The patient's medical history included diabetes mellitus, benign prostatic hyperplasia, and hypertension. He had an extensive history of smoking tobacco (60 pack-years), though he had quit 15 years before this presentation. He also had a 5-year history of using chewing tobacco and occasionally drank alcohol. Physical examination revealed poor dentition but was otherwise unremarkable. Chest x-ray showed no evidence of pulmonary nodules, consolidation, or infiltrates. Soft tissue computed tomography of the neck showed right vocal cord irregularity and enlargement compared with the left. Direct laryngoscopy revealed a verrucous lesion of the right true vocal fold that approached the anterior commissure and arytenoid. No extension into the ventricle or subglottis was seen. The vocal cord also showed decreased mobility. By gross examin ation, the lesion was thought to be a malignancy. Excisional biopsy was done, and histopathologic examination showed only acute and chronic inflammation of the laryngeal mucosa with focal dyskeratosis of the epithelium. No malignant lesion was identified.

Several months later, a repeat laryngoscopic evaluation showed recurrence of the lesion. The lesion occupied approximately 80% of the length of the right cord and was three times the width of the normal-appearing left vocal cord. The lesion was excised and submitted for pathologic examination. Histologic examination of the laryngeal biopsy showed mild acute and marked granulomatous inflammation with giant cell formation in the submucosa (Fig. 1). Pseudoepitheliomatous hyperplasia characterized by proliferating strands of squamous epithelium protruding into the dermis was also present (Fig. 2). Methenamine silver stain showed numerous yeasts measuring approximately 4 to 10 [micro]m (Fig. 3). Also, capsules surrounding the yeasts stained pink with mucicarmine stain, allowing a diagnosis of laryngeal infection by C. neoformans. Kinyoun stain was negative for acid-fast organisms, and no malignancy was identified. The patient received a 6-week course of fluconazole antifungal therapy, and he was tested for HIV, th e results of which were negative. The hoarseness resolved, and there has been no evidence of recurrence during the subsequent 24 months. In light of the microscopic findings of the second laryngeal biopsy, additional tissue sections of the original biopsy were obtained and showed a small focus of granulomatous inflammation. The methenamine silver and mucicarmine stains of these sections identified the cryptococcal yeasts.

Discussion

Although viral laryngitis is the most common infectious cause of hoarseness, primary mycotic laryngeal infections have been described, most of them existing in the tissues as yeasts. These include Candida species (C. albicans is the most common), H capsulatum, Coccidioides immitis, B. dermatitidis, Paracoccidioides brasiliensis, and C. neoformans. (2) Mycotic infections of the larynx tend to arise, though not exclusively, in immunocompromised hosts and also tend to occur as a result of dissemination of the organism. The exception is laryngeal candidiasis, a disease that usually coexists with oral candidiasis, (2) and probably occurs as a result of direct extension from the oral lesions. The histologic appearance can be similar for each of these infections, since many exhibit pseudoepitheliomatous hyperplasia of the squamous mucosa, and granulomatous inflammation in the submucosal region. Identification can be achieved with culture or microscopic examination of biopsy-obtained tissue in conjunction with specia l stains such as methenamine silver or mucicarmine if C. neoformans is suspected.

Relative to other fungal infections of the larynx, C. neoformans laryngitis is uncommon. Cryptococcus neoformans usually occurs as a primary pulmonary infection that can potentially disseminate in an immunocompromised host to body regions such as the central nervous system, meninges, bone, or SC tissue. Although the majority of cryptococcal infections occur in immunocompromised patients, occasionally hosts with a relatively intact immune system can be infected as well. Cryptococcus neoformans is identified in tissue sections as eosinophilic or lightly basophilic yeasts that vary in size from 2 to 20 mm. These yeasts possess capsules that stain positively with mucicarmine and cell walls that stain positively with methenamine silver. In immunocompetent patients, C. neoformans usually elicits a granulomatous reaction. whereas in an anergic patient, the host reaction may be greatly diminished (3) Methods of diagnosing C. neoformans infection in the cerebrospinal fluid include India ink preparation, culture, or an tigen detection by latex agglutination.

Cases of laryngeal cryptococcosis have been previously described. (4-7) Features of these cases are outlined in Table 1. Common characteristics among these cases include history of hoarseness and cough, erythema and edema of the vocal cord, verrucous gross appearance, and pseudoepitheliomatous hyperplasia of the laryngeal mucosa seen on microscopic examination. Although cryptococcal infections generally are most common in AIDS patients, only 1 of 5 patients with laryngeal cryptococcosis (including our case) was severely immunocompromised. Also noteworthy is that the 5 reported cases of laryngeal cryptococcosis were from states in the southeastern region of the country, although no reported geographic distribution of cryptococcosis has been described.

Laryngeal involvement may have arisen either from a hematogenous route with spread from a primary focus such as the lung or from direct implantation by inhaled aerosolized organisms. We suspect that laryngeal infection in this case was from direct inoculation for two reasons. One is that other than diabetes mellitus that appeared to be well controlled, the patient was not immunocompromised in any way and hence risk of cryptococcal dissemination was probably low. The second is that the patient had a nonproductive cough possibly due to primary cryptococcal infection of the lung at approximately the same time as his hoarseness. With synchronous occurrence of these symptoms, we can at least hypothesize that inoculation of the lung and larynx occurred at the same time.

Mycotic laryngitis mimicking a malignant process as it did in this case has also been described in reports of other mycotic laryngeal infections. In one case of an HIV-infected patient, the gross appearance of the vocal cords was thought initially to represent Kaposi's sarcoma, (7) however, microscopic examination identified cryptococcal yeasts with granulomatous inflammation. Laryngeal blastomycosis and aspergillosis have been reported to mimic laryngeal carcinoma. (8, 9) A case of laryngeal histoplasmosis strongly resembled papillomas on laryngoscopy. (10) Given the verrucous appearance of a fungal infection in the larynx, the potential to confuse a mycotic infection with laryngeal carcinoma can be high. The clinical evaluation of hoarseness, including history, physical examination, and direct visualization of the larynx will often provide enough clues to lead to a presumptive diagnosis. Our case, however, illustrates that histopathologic examination is often necessary to make an accurate diagnosis.

Conclusion

We have presented a rare case of laryngeal cryptococcosis that mimicked laryngeal carcinoma. Likely, this cryptococcal infection occurred by direct implantation of the organism rather than by hematogenous dissemination, given the relatively intact immune system of the patient. This case emphasizes the need for biopsy confirmation, since other pathologic entities including fungal infections may clinically mimic a malignant process.

Table 1

Summary of five reported cases of laryngeal cryptococcosis

Series                          Age (yr)/
(ref. no.)                         Sex

Reese and Colclasure, 1975 (5)    47/M


Smallman et al, 1989 (4)          31/F

Browning et al, 1992 (7)          46/M

Isaacson and Frable, 1996 (6)     87/M



McGregor et al, 2003              60/M



Series                          Possible risk
(ref. no.)                      factors

Reese and Colclasure, 1975 (5)  Exposure to chicken manure,
                                 congestive heart failure

Smallman et al, 1989 (4)        None

Browning et al, 1992 (7)        AIDS, recent cryptococcal
                                 pneumonia
Isaacson and Frable, 1996 (6)   High dose of inhaled
                                 corticosteroids, chronic
                                 obstructive plumonary disease,
                                 tobacco smoker
McGregor et al, 2003            Tobacco smoker, tobacco chewer,
                                 diabetes mellitus


Series
(ref. no.)                      Location

Reese and Colclasure, 1975 (5)  Arkansas


Smallman et al, 1989 (4)        Alabama

Browning et al, 1992 (7)        Georgia

Isaacson and Frable, 1996 (6)   Virginia



McGregor et al, 2003            Texas



Series
(ref. no.)                      Gross description

Reese and Colclasure, 1975 (5)  Marked laryngeal edema and glottic
                                 obstruction; multiple white,
                                 raised mucosal lesions
Smallman et al, 1989 (4)        "Warty" 0.5-cm lesion

Browning et al, 1992 (7)        Erythema and edema from vocal cord
                                 to anterior commissure
Isaacson and Frable, 1996 (6)   Bilateral edematous and
                                 erythematous vocal cords,
                                 exudative white vocal cord lesion

McGregor et al, 2003            Verrucose vocal cord lesion



Series
(ref. no.)                      Microscopic description

Reese and Colclasure, 1975 (5)  Pseudoepitheliomatous hyperplasia
                                 and granulomatous inflammation

Smallman et al, 1989 (4)        Pseudoepitheliomators hyperplasia
                                 and granulomatous inflammation
Browning et al, 1992 (7)        Granulomatous inflammation

Isaacson and Frable, 1996 (6)   Pseudoepitheliomatous hyperplasia
                                 and granulomatous inflammation


McGregor et al, 2003            Pseudoepitheliomatous hyperplasia,
                                 granulomatous inflammation, and
                                 mild acute inflammation

Series
(ref. no.)                      Treatment

Reese and Colclasure, 1975 (5)  Amphotericin B (2 g over 30 d)


Smallman et al, 1989 (4)        None (refused treatment)

Browning et al, 1992 (7)        Amphotericin B (120 mg X 4 d) then
                                 fluconazole
Isaacson and Frable, 1996 (6)   Fluconazole (400 mg) X 8 wk)



McGregor et al, 2003            Fluconazole X 6 wk

Accepted December 17, 2001.

References

(1.) Berke GS, Kevorkian KF. The diagnosis and management of hoarseness. Compr Ther 1996;22:251-255.

(2.) Vrabec DP. Fungal infections of thc larynx. Otolaryngol Clin North Am 1993;26:1091-1114.

(3.) Chandler FW, Watts JC: Cryptoccocosis, in Connor DH, Chandler FW, Schwartz DA, Manz HJ Lack EE (eds): Pathology of Infectious Diseases. Stamford, CT, Appleton & Lange, 1997, vol 1, pp 989-997.

(4.) Smallman LA, Stores OP, Watson MG, Proops DW. Cryptococcosis of the larynx. J Laryngol Otol 1989;103:214-215.

(5.) Reese MC, Colclasure JB. Cryptococcosis of the larynx. Arch Otolaryngol 1975;101:698-701.

(6.) Isaacson JE, Frable MA. Cryptococcosis of the larynx. Otolaryngol Head Neck Surg 1996;114:106-109.

(7.) Browning DG, Schwartz DA, Jurado RL. Cryptococcosis of the larynx in a patient with AIDS: An unusual cause of fungal laryngitis. South Med J 1992;85:762-764.

(8.) Payne J, Koopmann CF Jr. Laryngeal carcinoma--or is it laryngeal blastomycosis? Laryngoscope 1984;94:608-611.

(9.) Kheir SM, Flint A, Moss JA. Primary aspergillosis of the larynx simulating carcinoma. Hum Pathol 1983;14:184-186.

(10.) Sataloff RT, Wilborn A, Prestipino A, et al. Histoplasmosis of the larynx. Am J Otolaryngol 1993;14:199-205.

RELATED ARTICLE: Key Points

* Cryptococcus neoformans usually occurs as a primary pulmonary infection in immunocompromised hosts and can disseminate to other body regions.

* Immunocompetent hosts may also develop cryptococcal infection as occurred in this case.

* Laryngeal cryptococcosis as well as other laryngeal mycotic infections may be misdiagnosed as a malignancy if the diagnosis is based purely on clinical examination and imaging studies.

* Histopathologic examination of a biopsy can provide a correct diagnosis by demonstrating yeasts showing staining with the Gomori methenamine silver and mucicarmine stains.

* Laryngeal cryptococcosis may occur by direct inoculation from a primary pulmonary infection or by hematogenous dissemination.

From the Department of Pathology, Baylor College of Medicine, and Ben Taub General Hospital, Houston, TX.

Reprint requests to Deborah Citron, MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9601-0074