Laryngeal Manifestations of Paracoccidioidomycosis (South American Blastomycosis)

ORIGINAL ARTICLE Laryngeal Manifestations of Paracoccidioidomycosis (South American Blastomycosis)

Geraldo Druck Sant’Anna, MD; Marcelo Mauri, MD; Jaime Luis Arrarte, MD; Humberto Camargo, Jr, MD

Objective: To report clinical manifestations, diagno- (43% [3/7]) were alcohol users. Clinical manifestations sis, and epidemiologic characteristics of laryngeal para- were dysphonia (86% [6/7]), dyspnea (71% [5/7]), dys- coccidioidomycosis. phagia (43% [3/7]), and cough (29% [2/7]). Laryngeal examination revealed ulcerative lesions with a mulberry- Design: Case series. like appearance in 3 patients and vegetative lesions in 4 patients. Many had multiple laryngeal lesions with in- Settings: Tertiary care institutional hospital. volvement of the true and false vocal cords, the epiglottis, and the arytenoid and interarytenoid areas. The first Patients: We reviewed the hospital records of 7 diagnostic impression was carcinoma in all patients. patients with laryngeal paracoccidioidomycosis diagnosed by histopathological examination. Conclusions: Laryngeal paracoccidioidomycosis may be a difficult diagnosis for the unsuspecting clinician to make. Main Outcome Measure: Clinical manifestations of Examination of the larynx can reveal lesions similar to laryngeal paracoccidioidomycosis. laryngeal cancer; therefore, diagnosis of carcinoma must be ruled out by histopathological examination or cul- Results: All patients were men and were middle-aged ture of a specimen. (range, 43-65 years), and most (86% [6/7]) were farm workers. All 7 patients regularly used tobacco, but only Arch Otolaryngol Head Neck Surg. 1999;125:1375-1378

ARACOCCIDIOIDOMYCOSIS eas that are contiguous to areas in which (South American blastomy- the disease incidence is very low.2 We be- cosis) is an uncommon, pro- lieve, however, that the true incidence of gressive, and systemic my- P brasiliensis infection is underestimated cosis that is caused by and that there are more cases than have Paracoccidioides brasiliensis and can be fa- been reported. The diagnosis is fre- P 1 tal if untreated. The disease is restricted quently not made until culture or histo- to populations in Latin America and is dis- pathological examination of a specimen is tributed heterogeneously throughout the carried out, owing to the difficulty in di- continent.2-4 Endemicity centers in re- agnosing unsuspected paracoccidioido- gions with relatively well-defined ecologi- mycosis. Therefore, asymptomatic cases cal characteristics (ie, the tropical and sub- usually are not diagnosed. tropical forests, where temperatures are Systemic mycoses are potentially se- mild and humidity is relatively high and rious and often lethal infections seen constant throughout the year). Although mainly in underdeveloped countries or in cases have been reported in North immunocompromised subjects.9 The di- America, Europe, and Asia, these pa- agnosis and treatment of laryngeal le- tients had previously been residents in sions is of increasing importance because countries where the disease is endemic.5 of the growing numbers of persons who The highest number of cases have are immunocompromised.10,11 However, been reported in Brazil, Colombia, Argen- the estimated incidence of paracoccidioi- From the Department of 6,7 Otorhinolaryngology, Fundac¸a˜o tina, and Venezuela. The number of in- domycosis among people with the ac- Faculdade Federal de Cieˆncias fected individuals in the entire area of en- quired immunodeficiency syndrome 12 Me´dicas de Porto Alegre, demicity, where 90 million people (AIDS) in Brazil is low (0.09%). The scar- Complexo Hospitalar Santa currently live, is approximately 10 mil- city of reported cases of paracoccidioido- Casa, Porto Alegre, Brazil. lion8; the disease incidence is high in ar- mycosis in people with AIDS might be ex-

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We reviewed the hospital records of 7 patients with laryngeal paracoccidioidomycosis confirmed by histopathological examination. All patients were Bra- zilians, admitted to Department of Otorhinolaryn- gology of Fundac¸a˜o Faculdade Federal de Cieˆncias Me´dicas de Porto Alegre, Complexo Hospitalar Santa Casa, Porto Alegre, Brazil, for an evaluation of their laryngeal problems between January 1994 and July 1997. The patients’ records were reviewed for age, sex, race, occupation, human immunodeficiency vi- rus (HIV) status, presenting symptoms, initial diagnostic impression, site of involvement, and evi- dence of concomitant pulmonary disease on chest Figure 1. Paracoccidioidomycosis lesion, showing a mulberrylike appearance with supraglottic, glottic, and infraglottic involvement. radiograms.

the true vocal folds in 4 (57%), epiglottic involvement in 2 (29%), involvement of the false vocal folds in 3 (43%), plained by the widespread use of trimethoprim- arytenoid involvement in 3 (43%), interarytenoid area sulfamethoxazole as prophylaxis for Pneumocystis carinii involvement in 2 (29%), and infraglottic involvement in pneumonia; this agent is also very effective against P 2 (29%). brasiliensis.2 We reviewed the hospital records of 7 patients with COMMENT laryngeal blastomycosis that was first diagnosed as a squa- mous cell carcinoma; subsequent examination of biopsy The term blastomycosis has sometimes been taken to in- specimens for these patients proved that the symptoms were clude a range of granulomatous systemic mycoses, in- caused by paracoccidioidomycosis. We present a detailed cluding South American blastomycosis (paracoccidioi- analysis of these cases and a discussion of the pathogen- domycosis or Lutz-Splendore-Almeida disease), North esis of laryngeal paracoccidioidomycosis, its microbio- American blastomycosis (Gilchrist disease), coccidioi- logic aspects, its clinical presentation, and treatment. domycosis, and cryptococcosis, but it is generally restricted to the South American and North American forms 1 RESULTS of blastomycosis. The age and sex distribution of clinical cases is pecu- All patients were adult men, middle-aged and older (range, liar. Paracoccidioidomycosis is rare in children and teen- 43-65 years; median, 53 years); 57% (4/7) were white, agers, and most patients are aged 30 years or older. Men 43% (3/7) were black, and 86% (6/7) were employed in are more commonly afflicted than women at a mean ratio low-income occupations that involve work outdoors, of- of 15:1. This is in contrast to the infection rate as deter- ten farming. All patients regularly used tobacco, but only mined by a paracoccidioidin skin test, which is similar for 43% (3/7) used alcohol. both sexes; however, when the disease occurs in prepu- These patients had a several-month history of bertal patients, there is no correlation with sex.6 Studies symptoms that resembled those of upper respiratory have also indicated that the progression of paracoccidioi- tract infection before seeking medical care (range, 2-22 domycosis is less frequent in women once they reach pu- months; median, 9 months). Laryngeal symptoms were berty because of the protective role that estrogen plays by identified in all patients; the prominent presenting inhibiting the transition of conidia and mycelia to yeast form, symptom was hoarseness (86% [6/7]), followed by dys- a critical step in the pathogenesis of the disease.2,13,14 The pnea (71% [5/7]), odynophagia (43% [3/7]), and cough occupational distribution reveals that paracoccidioidomy- (29% [2/7]). Fatigue, weight loss, and fever were mini- cosis has a predilection for agricultural workers.5 Alcohol- mal manifestations. All patients had alterations on chest ism has been shown to be an important predisposing fac- radiograms, but only 2 patients (29%) had pulmonary tor. The scarcity of reported cases of paracoccidioidomycosis involvement caused by paracoccidioidomycosis. Five in people with AIDS may be explained by the widespread patients were HIV-negative, and for 2 patients HIV sta- use of trimethoprim-sulfamethoxazole as prophylaxis for tus was not established. P carinii pneumonia; this agent is also very effective against Two patients underwent direct laryngoscopy and 5 P brasiliensis.2 underwent flexible fiberoptic laryngoscopy; biopsies were Paracoccidioidomycosis is a chronic mycosis; its later performed for all patients. The first diagnostic impres- forms are fungus infections of viscera, lymph nodes, and sion was laryngeal cancer in all patients. The findings of mucocutaneous tissues.1 The disease is prevalent in South these examinations showed ulcerated lesions with a mul- America, particularly in Brazil, as well as in portions of berrylike appearance in 3 patients and vegetative le- Mexico and Central America. The occasional reports of sions in 4 patients (Figure 1). Many patients had mul- cases occurring within the United States are probably tiple laryngeal lesions. Examination revealed lesions of caused by infection in patients exposed to contami-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 2. Laryngeal biopsy specimen with ulcerated mucocutaneous lesion, Figure 3. Laryngeal biopsy specimen with double-contoured fungi inflammatory cells, and double-contoured, budding yeast cell surrounded by inflammatory cells and multinucleate giant cells (hematoxylin-eosin, original magnification ϫ150). (hematoxylin-eosin, original magnification ϫ800).

nated soil while traveling in endemic areas.15-17 The disease, this is not always the case. Lesions of the larynx can ease has long periods of latency, as demonstrated by cases be diffuse, with involvement of the whole larynx, or re- reported outside of the endemic area; some of these pa- stricted to specific sites, such as the anterior or poste- tients developed overt disease symptoms 30 or more years rior commissure, false vocal cord, epiglottis, and infra- after leaving the endemic regions.5 Primary cutaneous glottis. The mode of dissemination is either hematogenous paracoccidioidomycosis is exceedingly rare. The more fre- or direct exposure from infected sputum.7 quent primary site of infection is the lung; pulmonary The cornerstone for the diagnosis of laryngeal para- disease is complicated by cavitation in approximately one coccidioidomycosis is the biopsy (Figure 2 and Figure 3). third of patients.17 Dissemination from the pulmonary fo- Microscopic examination will reveal acanthosis, pseudo- cus may cause mucous membrane ulcerations and/or ver- epitheliomatous hyperplasia, inflammatory cells, multi- rucous lesions of the skin.17 nucleate giant cells, and round, double-contoured single- Paracoccidioides brasiliensis is a thermally dimorphic budding organisms.7 If direct examination in potassium fungus known to exist only in its asexual state. The fun- hydroxide preparation or hematoxylin-eosin staining does gus grows as a yeast in host tissues and in the laboratory not reveal the organism, staining biopsy specimens with when incubated at 37°C; growth from a single mother cell Grocott-Gomori methenamine-silver may be helpful.16,17 becomes apparent after 10 to 15 days of incubation. In the A culture of the organism can be diagnostically useful, but yeast phase, the colonies are soft, wrinkled, and cream- P brasiliensis grows extremely slowly, even on blood agar, colored and are composed of yeast cells of different sizes although in this respect Sabouraud dextrose agar is pre- (4-30 µm), usually oval to elongated with multiple bud- ferred.1,7,19 Serological procedures applied to paracoccidi- ding cells. The mycelial form grows after 20 to 30 days of oidomycosis have allowed its early diagnosis and made it incubation at room temperature. Colonies are white, small, possible to treat the disease appropriately.22 However, se- and irregular and are covered by short aerial mycelia that rological tests (complement fixation and skin tests) are un- often adhere to the agar, breaking its surface. Diagnosis by reliable, since many patients with positive stains and cul- culture and histological examination relies on the most char- tures have negative complement fixation test results.6 Del acteristic feature of the yeast form: the pilot’s-wheel ap- Negro et al22 have reported that agar and agarose gel pre- pearance (ie, a mother cell surrounded by multiple periph- cipitation tests (double immunodiffusion and counterim- eral daughter cells).15,18,19 munoelectrophoresis) have greater sensitivity (91.3% and The diagnosis of laryngeal paracoccidioidomycosis 95.6%, respectively), and maximum specificity (100%) may be difficult for the unsuspecting clinician. The pa- compared with complement fixation (sensitivity, 71.1%; tient may have a several-month history of symptoms that specificity, 95.4%) and indirect immunofluorescence (sen- resemble those of upper respiratory tract infection, with sitivity, 65.2%; specificity, 90%). A polymerase chain re- an associated hoarse voice, productive cough, and occa- action assay, a promising diagnostic tool, has been devel- sional hemoptysis, as well as low-grade fever, weight loss, oped to detect small amounts of DNA from P brasiliensis.2 and general malaise. Laryngeal examination may reveal The differential diagnosis of paracoccidioidomyco- ulceration, diffuse erythema, and/or a fungating lesion sis usually includes carcinoma, tuberculosis, lupus ery- very similar to carcinoma.7,16-18,20 Paracoccidioidomyco- thematosus, North American blastomycosis, histoplas- sis is a polymorphic disease with a wide clinical gamut, mosis, coccidioidomycosis, sarcoidosis, syphilis, Wegener ranging from localized disease to disseminated, acute, and granulomatosis, granuloma inguinale, actinomycosis, chronic forms.7 Sites of dissemination include skin, bones, leishmaniasis, and other granulomatous disorders.* As urogenital tract, gastrointestinal tract, brain, abdominal the literature reveals, the differentiation between squa- lymph nodes, spleen, liver, and the adrenal glands.7,9,15,21 Although laryngeal involvement with paracoccidioidomycosis is usually associated with active pulmonary dis- *References 1, 6, 12, 14, 16, 19, 20, 23-25.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 mous cell carcinoma and paracoccidioidomycosis may 5. Franco MF, Mendes RP, Moscardi-Bacchi TV, et al. Paracoccidioidomycosis. Clin be difficult.7 The key to the correct diagnosis is a high Trop Med Commun Dis. 1989;4:185-220. 6. Restrepo A. The ecology of Paracoccidioides brasiliensis: a puzzle still un- index of suspicion on the part of the clinician and an un- solved. Sabouraudia. 1985;23:323-334. relenting search for the fungal organisms. Despite the oc- 7. Payne J, Koopmann CF. Laryngeal carcinoma—or is it laryngeal blastomycosis. currence of cases that mimic cancer, paracoccidioido- Laryngoscope. 1984;94:608-611. mycosis should be suspected when there are associated 8. Greer DL, Restrepo A. La epidemiologia de la paracoccidioidomycosis. Bol Ofi- lung symptoms and when a patient has had previous con- cina Sanit Panam. 1977;83:428-445. 9. Sposto MR, Scully C, Almeida OP, Jorge J, Graner E, Bozzo L. Oral paracoccidi- tact with endemic areas. Repeated multiple biopsies may oidomycosis: a study of 36 South American patients. Oral Surg Oral Med Oral be necessary to obtain the organism both for histopatho- Pathol Oral Radiol Endod. 1993;75:461-465. logical confirmation and for culture growth. 10. de Almeida OP, Scully C. Oral lesions in the systemic mycoses. Curr Opin Dent. A range of antimicrobial agents can be effective treat- 1991;1:423-428. 11. Scully C, de Almeida OP. Orofacial manifestations of the systemic mycoses. ments for paracoccidioidomycosis. Intravenous ampho- J Oral Pathol Med. 1992;21:289-294. tericin B therapy can be curative. Sulfadiazine or sulfi- 12. Ministe´rio da Sau´de-Brasil. Bol Epidemiol AIDS. 1992;5:13-16. soxazole therapy can arrest disease progress, but relapses 13. Marques SA, Conterno LO, Sgarbi LP, et al. Paracoccidioidomycosis associated occur unless continuous therapy is used.1 Amphotericin with acquired immunodeficiency syndrome: report of seven cases. Rev Inst Med B therapy plus a sulfonamide, such as sulfamethoxypyri- Trop Sao Paulo. 1995;37:261-265. 14. Salazar Me, Restrepo A, Stevens DA. Inhibition by strogens of conidium-to- dazine, is even more effective. Paracoccidioidomycosis also yeast conversion in the fungus Paracoccidioides brasiliensis. Infect Immun. 1988; responds well to oral ketoconazole, itraconazole, flucona- 56:711-713. zole, or intravenous miconazole therapy.1,16 Fluconazole, 15. Dismukes WE. Paracoccidioidomycoses. In: Wyngaarden JB, Smith LH, Ben- 200 to 400 mg daily, administered orally, resulted in a re- nett JC, eds. Cecil Tratado de Medicina Interna. 19th ed. Rio de Janeiro, Brazil: sponse rate of better than 90% and may ultimately be the Guanabara e Koogan; 1993:1933-1934. 16 16. Hollander H. Infectious diseases: mycotic. In: Tierney LM, McPhee SJ, Pa- drug of choice. When the correct diagnosis is made, suc- padakis MA, eds. Current Medical Diagnosis and Treatment. 33rd rev int ed. East cessful treatment is possible; therefore, a high level of clini- Norwalk, Conn: Appleton & Lange Paramount; 1994:1243-1251. cal suspicion is required for patients with symptoms that 17. Hirsch BC, Johnson WC. Pathology of granulomatous diseases: mixed inflam- resemble those of upper respiratory tract infection who are matory granulomas. Int J Dermatol. 1984;23:585-597. from areas in which paracoccidioidomycosis is endemic. 18. Lacaz CS, Porto E, Martins JEC. Paracoccidioidomycoses. In: Micologia Me´dica. 8th ed. Saõ Paulo, Brazil: Sarvier Editora; 1991:248-261. 19. Lodi M, Azevedo JPM, Ko´s AO, et al. Blastomicose de laringe. An Hosp Sider Accepted for publication July 2, 1999. Nac. January-March 1985;9:43-45. 20. Valle ACF, Aprigliano-Filho F, Moreira JS, Wanke B. 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