Laryngeal Cryptococcosis: Literature Review and Guidelines for Laser Ablation of Fungal Lesions

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Systematic Review Laryngeal Cryptococcosis: Literature Review and Guidelines for Laser Ablation of Fungal Lesions Jack Y. Jeng; Courtney M. Tomblinson, MD; Idris Tolgay Ocal, MD; Holenarasipur R. Vikram, MD; David G. Lott, MD Objectives/Hypothesis: To describe the demographics, clinical manifestations, diagnosis, treatment, and outcomes of laryngeal cryptococcosis. Antifungal therapy guidelines are provided and the use of laser ablation is discussed. Data Sources: PubMed, OVID MEDLINE, and Embase databases and one patient who presented to our institution s otolaryngology department. Review Methods: A review of the English-language international medical literature was conducted using the terms ( larynx or laryngeal diseases ) and ( Cryptococcus or cryptococcosis ) to identify reported cases of laryngeal cryptococcosis. Databases were searched from inception through January Results: Eighteen cases were identified and reviewed, including the first reported case of potassium-titanyl-phosphate laser ablation. All patients presented with hoarseness, and two (11%) presented with acute airway obstruction that required tracheotomy. Six patients (33%) were immunocompromised, including three (17%) who had an underlying human immunodeficiency virus infection. Seven cases (39%) described an exophytic mass. Histopathology indicated pseudoepitheliomatous hyperplasia in seven of the 17 reported results (41%). Methenamine silver stain was used in 12 of the 15 described cases (80%) to identify the fungus. Lumbar puncture results were reported for seven patients, none of whom had meningitis. Antifungal therapy was used in 15 cases (83%), and two (11%) received additional laser ablation treatment. Eleven patients (61%) had complete resolution. Conclusions: Laryngeal cryptococcosis is a rare cause of persistent hoarseness. Most patients have complete resolution after treatment. For complex and obstructive cases, laser ablation coupled with antifungal therapy can successfully manage laryngeal cryptococcosis in select patients. Key Words: Cryptococcosis, Cryptococcus, fluconazole, hoarseness, infection, larynx, laser therapy. Level of Evidence: NA Laryngoscope, 126: , 2016 INTRODUCTION Cryptococcus is an opportunistic fungus that most commonly infects the lungs. 1 Localized laryngeal cryptococcal infection is extremely rare, with only 17 cases reported to date The most common presenting symptom is hoarseness, with most patients having complete resolution after treatment with antifungal therapy. We describe the first case of recalcitrant laryngotracheal From the Department of Radiology (C.M.T.); and Division of Anatomic Pathology (I.T.O.), Mayo Clinic, Scottsdale, Arizona; Division of Infectious Diseases (H.R.V.); and Division of Otolaryngology Head and Neck Surgery (D.G.L.), Mayo Clinic Hospital, Phoenix, Arizona; Mayo Medical School (J.Y.J.), Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A. Presented in part at the Fall Voice Conference, San Antonio, Texas, U.S.A., October 23 25, The authors have no funding, financial relationships, or conflicts of interest to disclose. Editor s Note: This Manuscript was accepted for publication September 24, Send correspondence to David G. Lott, MD, Division of Otolaryngology-Head and Neck Surgery, Mayo Clinic Hospital, 5777 E. Mayo Blvd, Phoenix, AZ lott.david@mayo.edu DOI: /lary cryptococcal infection treated with oral fluconazole and potassium-titanyl-phosphate (KTP) laser ablation. METHODS Data Sources We conducted a comprehensive search of the international medical literature by using databases from PubMed (US National Library of Medicine database), OVID MEDLINE, and Embase. We searched from database inception through January Only English-language reports were included in this study. In addition to the reviewed literature, we describe one patient who presented to our institution s otolaryngology department. Review Methods We initially used PubMed to identify articles reporting patients with cryptococcal infection of the larynx. The following medical subject headings terms were used: ( larynx or laryngeal diseases ) and ( Cryptococcus or cryptococcosis ). This search yielded 17 articles. Upon further review, we excluded four because they were in a foreign language and two because they did not describe laryngeal cryptococcosis. We conducted a similar search using OVID MEDLINE to identify additional articles. This search yielded 19 results, of 1625

2 Fig. 1. Office transnasal laryngoscopy showed extensive white exophytic lesions growing on the supraglottic larynx and true vocal folds bilaterally. which three were unique publications not identified by the PubMed search. Two of the three articles described laryngeal cryptococcosis. We conducted a final search using Embase to identify additional articles. This search yielded 28 results, of which 13 were unique publications not found in the two prior searches. Eleven were excluded because they did not describe laryngeal cryptococcosis. Reference lists of all articles were reviewed to identify any additional cases. The corresponding author of a review article was contacted for a copy of references not listed at the end of the article. 12 Altogether, our search strategy yielded 15 articles describing 17 cases After including our case, the total cohort consisted of 18 cases of laryngeal cryptococcosis. infection of the underlying tissues. Mixed inflammatory infiltrate was present, but no well-formed granulomas were evident. Microorganisms stained strongly with Grocott-Gomori methenamine silver stain and mucicarmine stain showed strong positivity, particularly at the periphery of the yeast forms, denoting capsules. The stains showed occasional budding but no hyphae formation (Fig. 2). Culture of the lesion isolated Cryptococcus neoformans. To improve medical management, the KTP laser was used to debulk involved areas. Photoablation was performed on a single, large lesion covering nearly the entire surface of the right true vocal fold (without disrupting the superficial lamina propria) and multiple lesions on the right vestibular fold, right side of the interarytenoid space, and the left vocal process. To prevent formation of an anterior glottic web, the anterior left true vocal fold was not treated. Bronchoscopy revealed similar lesions in the posterolateral right tracheal wall and down the length of the trachea. An infectious disease specialist evaluated the patient 4 days after her procedure. Serum cryptococcal antigen titer was abnormal at 1:8, an antibody test for human immunodeficiency virus (HIV) was negative, and a lumbar puncture revealed normal cerebrospinal fluid without evidence of cryptococcal meningitis. The patient initiated treatment with oral fluconazole (400 mg daily). After the KTP laser procedure and 3.5 weeks of medical therapy, the patient reported marked improvement in her voice. Repeat office transnasal laryngoscopy showed only a few small Report of a Case A 71-year-old woman from Ohio, with a medical history significant for chronic obstructive pulmonary disease using inhaled corticosteroids and topical nystatin for episodic oral thrush, presented with cough and worsening hoarseness that began 2 months earlier. At an initial visit to her local otolaryngologist, exophytic lesions on the posterior larynx and right false vocal fold were noted. Biopsy showed necrotic debris and microorganisms consistent with Cryptococcus species. She completed 2 weeks of oral fluconazole treatment (100 mg daily) without improvement and was subsequently referred to our institution. Upon presentation to our clinic, the patient had a severely dysphonic voice without dyspnea or dysphagia. She denied fever, chills, headache, visual disturbances, or a stiff neck, and physical examination findings were unremarkable. She did not have a history of tobacco use. The patient reported exposure to bird droppings from a nearby feeder and gardening before symptom development. Office transnasal laryngoscopy and stroboscopy showed extensive white exophytic lesions growing on the right vestibular fold, arytenoids bilaterally, interarytenoid area, and true vocal folds bilaterally (Fig. 1). The lesions covered most of the true vocal folds bilaterally, resulting in severe loss of pliability and mucosal wave. A computed tomography scan of the chest showed calcified mediastinal lymph nodes without evidence of pulmonary cryptococcal infection. Due to the recalcitrant nature of the disease, the patient was brought to the operating room for definitive diagnosis and debulking. Biopsy at the level of the true vocal folds showed inflamed squamous mucosa and extensive fungal microorganism 1626 Fig. 2. (Upper panel) Grocott-Gomori methenamine silver stain on tissue section from the biopsy showed strong staining of abundant yeast forms with budding (red arrows) (original magnification, 3400). (Lower panel) Mucicarmine stains the periphery (black arrows) of the microorganisms, corresponding to the capsular staining of yeast forms in this biopsy section (original magnification, 3400).

3 TABLE I. Patient Characteristics and Presenting Symptoms of Laryngeal Cryptococcosis (n 5 18). Variable Value Fig. 3. Office transnasal laryngoscopy performed 3.5 weeks after laser ablation and fluconazole therapy showed marked improvement, with only a few small lesions on the right medial arytenoid. lesions on the right medial arytenoid (Fig. 3). Serum cryptococcal antigen titer decreased to 1:4 and liver function tests were normal. Stroboscopy performed 7 weeks after the procedure showed normal mucosal wave and pliability. Office laryngoscopy results are shown in Figure 4. Serum cryptococcal antigen titer was negative 3.5 months after initiating medical therapy. After 4 months, the patient s voice had completely recovered. She had a granuloma-like lesion above the right vocal process, but no cryptococcal lesions were evident. The granuloma resolved after a 90-day course of omeprazole and ranitidine. The patient completed a 6-month course of oral fluconazole therapy and remained asymptomatic. Office laryngoscopic examination 11 months later showed no recurrence of disease. RESULTS Eighteen laryngeal cryptococcosis cases were identified and reviewed Table I summarizes the patient characteristics and presenting symptoms. All patients presented with hoarseness, and two presented with acute airway obstruction that required tracheotomy. Almost half of the patients were using an inhaled corticosteroid at the time of infection, and six were immunocompromised, including three who had an underlying HIV infection. Fig. 4. Office transnasal laryngoscopy performed 7 weeks after laser ablation and fluconazole therapy showed complete resolution of lesions. Note a small granuloma on the right vocal process. Age, yr, median (range) 61 (31 87) Male sex, No. (%) 12 (67) Presenting symptom, No. (%)* Hoarseness 18 (100) Cough 4 (22) Acute airway obstruction requiring 2 (11) tracheotomy Duration of presenting symptoms, wk, 12 (3 104) median (range) Possible predisposing factors, No. (%)* Inhaled corticosteroid use 8 (44) Immunocompromised state Documented human immunodeficiency 3 (17) virus infection Oral corticosteroid use 3 (17) Current or prior tobacco use 6 (33) Exposure to bird droppings 3 (17) *Numbers may sum to more than the overall total and percentages may sum to >100% because some patients met multiple criteria. Table II summarizes clinical manifestations and diagnostic details. Laryngeal edema and erythema with white exophytic lesions are the most common Characteristic TABLE II. Clinical Manifestations and Diagnostic Details. No. of Patients (%)* Microlaryngoscopy finding (n 5 18) Airway edema 8 (44) Exophytic mass on or near vocal folds 7 (39) Airway erythema 6 (33) White lesions on or near vocal folds 6 (33) Histopathology (n 5 17) Granulomatous inflammation 10 (59) Pseudoepitheliomatous hyperplasia 7 (41) Inflammation without granulomas 4 (24) Positive stains (n 5 15) Grocott-Gomori methenamine silver 12 (80) Mucicarmine 10 (67) Alcian blue 5 (33) Periodic acid Schiff 3 (20) Positive culture for Cryptococcus neoformans (n 5 12) 5 (42) Positive cryptococcal serum 2 (22) antigen titer (n 5 9) Abnormal findings on cerebrospinal 0 (0) fluid (n 5 7) *Numbers may sum to more than the overall total and percentages may sum to >100% because some patients met multiple criteria. Includes culture from cerebrospinal fluid, blood, urine, sputum, bronchial washing, and/or biopsy specimen. 1627

4 Variable TABLE III. Treatments and Outcomes. Value Treatment, No. (%) (n 5 18) Antifungal therapy only 13 (72) Endoscopic polypectomy only 3 (17) Antifungal therapy and laser ablation 2 (11) Fluconazole treatment duration, median 8 (2 40) (range), wk (n 5 10) Duration of follow-up, mo, median 9 (0.5 24) (range) (n 5 16) Outcomes, No. (%) (n 5 18) Complete resolution 11 (61) Improvement 6 (33) Recurrence* 1 (6) Treatment resulting in complete resolution, No. (%) (n 5 11) Anti fungal therapy only 8 (73) Endoscopic polypectomy only 2 (18) Antifungal therapy and laser ablation 1 (9) *Patient declined treatment and was lost to follow-up. laryngoscopy findings. Grocott-Gomori methenamine silver and mucicarmine stains are positive in most patients. Of the nine tested patients, seven had negative serum cryptococcal antigen titers. Lumbar puncture results were reported for seven patients, none of whom had meningitis. Table III summarizes treatments and outcomes. Antifungal therapy was used in 15 cases, and two received additional laser ablation treatment. Fluconazole (400 mg daily) was the most commonly used medication. Only two patients (including ours) had a bronchoscopy performed, and both patients had lesions in the trachea. Most patients had complete resolution. DISCUSSION C neoformans is an encapsulated yeast that is found worldwide in soil. 16 It is abundant in pigeon feces and easily inhaled, making the lungs the most common site of infection. Cryptococcosis usually is a self-limited, subacute infection in healthy persons, but it can be lifethreatening in patients with acquired immunodeficiency syndrome if the central nervous system becomes infected. Cryptococcus gattii more commonly infects healthy hosts and is estimated to cause 70% to 80% of cryptococcal infections among immunocompetent patients. 14,16 C gattii is usually found in tropical and subtropical areas such as Australia and South America, and it is associated with certain eucalyptus trees. In the United States, it is most common in southern California. More recently, C gattii has been implicated as the cause of outbreaks in the Pacific Northwest. 17 Laryngeal cryptococcal infection is rare. Possible contributing factors include use of inhaled or oral corticosteroids, tobacco smoke, tuberculosis, HIV, or hepatitis C infection, diabetes mellitus, previous cryptococcal 1628 pneumonia, and exposure to pigeon feces, chicken manure, or eucalyptus trees Microlaryngoscopy and biopsy are necessary for diagnosis, and special stains such as Grocott-Gomori methenamine silver and mucicarmine may be required to detect fungal elements. Serum cryptococcal antigen titer may be useful for diagnosing and monitoring the treatment status of laryngeal cryptococcosis, as well as for determining the extent of the cryptococcal infection. HIV infection, other systemic immunosuppressive disorders, and disseminated cryptococcal disease should be excluded in all patients with possible laryngeal cryptococcosis. Many clinical microbiology laboratories do not distinguish between C neoformans and C gattii, but the latter should be suspected in immunocompetent patients from endemic regions. 17 The Infectious Diseases Society of America has published detailed guidelines for the management of cryptococcal infection. 18 These guidelines discuss cryptococcal infection in immunocompetent and immunocompromised hosts, with or without meningitis. In immunocompetent patients with nonmeningeal disease and without cryptococcemia, fluconazole (400 mg daily for 6 12 months) is recommended. After debulking lesions with the KTP laser, we followed this guideline for patient treatment. Use of Lasers for Laryngeal Cryptococcosis Our case is the second reported case of laser therapy in the management of cryptococcal laryngeal lesions, but to our knowledge, it is the first to report use of a KTP laser. Even though our patient had previously received oral antifungal medication, she did not have an adequate dose or duration of antifungal therapy, necessitating endoscopic laser surgery to both confirm the diagnosis and debulk the lesions. In addition to laser ablation, we prescribed fluconazole (400 mg daily) for 6 months and noted excellent results. Although our patient had complete resolution of symptoms, lasers should be used only in select patients and by a skilled surgeon. The KTP laser is widely used in the modern era as a tool for delicate, endoscopic laryngeal work. It falls broadly into the category of angiolytic lasers and has been proven more effective, reliable, and less expensive than the 585-nm pulse-dye angiolytic laser that was previously used in laryngeal surgery. 19 When used correctly, laser ablation preserves the tissue planes beyond the depth of the lesions, allowing clear differentiation between diseased and normal tissue. Laser surgery of the vocal folds requires great care to avoid inadvertent damage to the underlying lamina propria, which can potentially cause permanent scarring and dysphonia. Avoiding damage to the lamina propria can be especially difficult in patients with inflammation during active infection. Fungal infections of the laryngeal epithelium rarely invade into deeper structures; they are associated with angiogenesis and erythema, bringing an increased blood supply to the vocal fold epithelium. In contrast, the underlying lamina propria has a large component of water. Compared with the CO 2 laser, which is absorbed

5 by water, the KTP laser has a wavelength of 532 nm, which is selectively absorbed by hemoglobin. The KTP laser s angiolytic properties thereby allow preferential ablation of the epithelial structures while preserving the delicate, water-filled lamina propria below. For this reason, the surgeon s preference was to use the KTP laser to selectively photoablate our patient s vocal fold pathology. Nothing in the literature suggests preferential use of one laser over another for this rare disease. One purpose of this report is to add our laser experience to the literature by documenting that the KTP laser can be used with good results for the ablation of laryngeal cryptococcosis. Additionally, we wanted to demonstrate that on the basis of the two reported laser cases in the literature, lasers can be safely used for the management of this disease under the proper circumstances. It is important to note that medical antifungal therapy should remain the mainstay of treatment for this disease. Most cases resolved with oral fluconazole treatment (400 mg daily). 12 Candidates for endoscopic laser based laryngeal surgery should be selected carefully. Specifically, for patients with infectious diseases of the larynx, we propose using laser ablation only for patients with disease refractory to initial medical management or patients who present with bulky, exophytic lesions and could benefit from laser debulking. Debulking of this infected tissue, as was done for our patient, can accelerate improvement in voice, improve quality of life, and increase efficacy of oral fluconazole therapy. Two patients identified by our literature review presented with acute airway obstruction necessitating tracheotomy, which may have been avoidable with laser photoablation. 1,13 Given the expertise needed to safely perform photoablation of diseased tissue, we recommend that laser ablation be performed by a surgeon experienced in laser phonosurgery. CONCLUSION Cryptococcal infection of the larynx is a rare cause of persistent hoarseness but should remain in the differential diagnosis. Correct diagnosis is challenging because microlaryngoscopy, biopsy, and special stains may be necessary. The Infectious Diseases Society of America recommends treating these patients with oral fluconazole (400 mg daily for 6 12 months). Our experience suggests that KTP lasers should be considered in select patients with laryngeal cryptococcosis when used in conjunction with oral fluconazole. BIBLIOGRAPHY 1. Reese MC, Colclasure JB. Cryptococcosis of the larynx. Arch Otolaryngol 1975;101: Smallman LA, Stores OP, Watson MG, Proops DW. Cryptococcosis of the larynx. J Laryngol Otol 1989;103: 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: Frisch M, Gnepp DR. Primary cryptococcal infection of the larynx: report of a case. 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