Independent Researcher, Paterson, NJ 07533, USAUnited States
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Objective: The objective of this study was to present a review article about laryngeal histoplas-mosis. Data Sources: Published English-language literatures in PubMed and Google scholar. Review Methods: PubMed and Google scholar were systematically searched using search terms: laryngeal and histoplasmosia. Study Selection: We included studies about laryngeal histoplasmosis. Results: Forty studies were included in this study. The results showed that most patients are male over 40 years old, and most cases were reported from endemic areas. Hoarseness dysphagia and general symptoms were the common symptoms of laryngeal histoplasmosis. Laryngeal mass was the most common finding during laryngeal exam. Itracanzole was the most common medication used to treat this disease. Laryngeal histoplasmosis had a good prognosis, but some cases may need long-term treatment up to 1 year. Conclusion: Histoplasmosis is a rare fungal granulomatous disease that may mimic laryngeal malignancy or tuberculosis.
Primary laryngeal histoplasmosis is a rare disease. Less than 100 cases of laryngeal histoplas-
mosis have been reported in English literatures since it was first described in 1940 by Brown
and colleagues. The clinical symptoms and signs may mimic tuberculosis or laryngeal malig-
nancy.1
Literature review was conducted using PubMed (MEDLINE) and Google Scholar for English
articles. The following keywords were used: laryngeal and histoplasmosis.
All laryngeal histoplasmosis articles published after 1984 were included in the study.
Forty studies about laryngeal histoplasmosis were available in PubMed (MEDLINE) and
Google scholar in English literature (Table 1).
8 females in the study Chart 1 and 2.
phagia, dysphagia, sore throat or globus), 9 patients had difficulty in breathing (17%) (stridor or
Cough, Subramaniam Irregular left vocal cord mass 1 M 52 Weight loss, et al extending to the anterior commissure ketoconazole for 1 month Fatigue,
Sore throat
Dysphonia,
2 Dysphagia, General laryngeal inflammation, Right Ghosh et al M 50 General, vocal cord ulcerated nodules
Symptom
Diarrhea,
Sore throat, Granulomatous supraglottic mucosa Amphotericin then
Robayo et al M 7 Fever, which deforms the epiglottis and None changed to Itraconazole
Headache, partially obstructs the airway
Stridor
Pervez Katoch Friable growth in the cricoid region Fluconazole with 4 M 20 Dysphagia et al subglottic
Fever, Cough, 5 laryngeal surface of the epiglottis Pulmonary Voriconazole Smoker John et al 53 Weakness, M and the vocal cords
Weight loss,
6 Hoarseness, Carter et al F 73 lesions across the laryngeal epiglottis Seropositive RA
Stridor
7 Erythematous keratinizing mass In Smoker Giménez et al M 55 Fever
Weightloss, The superior right free edge of the
O’Hara et al M 78 Dysphagia, epiglottis showed an irregular mass Pulmonary Itraconazole for 9 months Travel
Night sweats with focal ulceration
9 Mouth swelling, Bist et al M 62 across the oropharynx, endolarynx Endemic Smoker
Weightloss, Showed that the mucosae at
Teoh et al M 70 Hoarseness, posterior one-third of both vocal folds Pulmomary DM Smoker
Dysphagia were irregular
Masoud et al M 60 Hoarseness Ulcerative growth in the left vocal cord None oral itraconazole for 12 TB Endemic
Weightloss, 12 vocal cords with granulomatous oral itraconazole Solari et al M 48 Stridor,
Dyspnea
Cough,
Weightloss,
Dyspnea,
M 70 Odynophagia, Ahumadau et surface of the epiglottis 13 Fatigue, al Anorexia,
Weight loss
Weightloss, The vocal process was thickened.
Smeets et al M 58 Hoarseness, granulation tissue on right ventricular None Itraconazole for 4 week Travel
Dysphagia area
Bouldouyre 15 M 65 Hoarseness right vocal cord, edema and et al
Amphotericin then None DM Smoker
Amphotericin then itra-
Disseminated conazole for 8 weeks Smoker
Immunosuppressant
medication for 12 months
Pharyngeal Endemic complete remession
Multiple ulcers on the
Adrenal gland treatment for 1 year Endemic
Gastrostomy, Multiple exophytic ulcer nodular Tracheostomy,
None Itraconzole for and vocal folds 2 months
None itraconzole both vocal cord Cirrhosis
Multiple exophytic nodular lesions Oral lesions Amphotericin then oral
Pharyngeal itraconazolefor 3 weeks and hypopharynx
Amphotericin then the oral itraconazole for
5 months
Amphotericin then
weeks
Epiglotitis, enlargement and mobile Amphotericin then Disseminated
histoplasmosis AIDS lesions deforming and infiltrating the with clinical improvement
glottis and subglottis in 1 month
Smoking
Immunosuppressant Vegetative lesion on the lingual amphotericin B then Pharyngeal drugs itraconazole for
12 months Travel
Non-specific inflammatory changes in Travel
Pulmonary Itraconazole for 6 months TB
hypertrophic vocal cord smoking
Weight loss Mackowiak et changes in the inter-arytenoid region Disseminated itraconazole for Addison’s disease 16 M 55 Hoarseness al involving the posterior part of Dysphagia
Sore throat 17 The vocal cords were swollen and Fechner et al M 44 Hoarseness,
Dysphagia
Weight loss,
Donegan et al M 69 Hoarseness, Left large epiglottic and glottis mass None Amphotericin for 6 weeks -
Dysphagia
2 Endophytic growth in 6 cases,
(30) exophytic growth in 2 cases and ulcer- There were no signs of
Weightloss, 19 8 M 4 aryepiglottic fold was the common site One case involvement 10 patients from Sonkhya et al Hoarseness, 2 F (40) of involvement (6 cases). Epiglottis pharyngeal Amphotericin in 3 cases. endemic area Dysphagia
4 only 1 case was with postcricoid and for 6 months
(50) subglottic lesion.
20 Hoarseness Whitish nodular lesions in the Cairoli et al F 35 and sore throat arytenoid cartilage and vocal cords
Larbcharoensub Hoarseness for 21 F 39 Glottic mass et al eleven months 22 Exophytic lesion Gulati, et al M 47 Painful ulcer
tongue
M 45 Hoarseness
23 Dyspnea, Indurated Glottis, supraglottic Troncoso et al M 30 Stridor, And Subglottic mass
Fever 24 Ulcerated mass that involved Le et al M 58 Dysphagia,
Weightloss
Weight loss, Vocal cord paresis and edema with
Sane et al M 55 Anorexia, small irregular nodule on the right Disseminated Amphotericin B for 1 year Endemic
Fever vocal cord
SOB Sore throat
26 Fever weight Ulcerative mass supraglottic edema Smoking Larsen et al M 63 loss stridor glottic
27 Laryngitis. non-specific changes in Sataloff et al F 44 Hoarseness
28 Dysphagia, Ragah et al M 55 Supraglottic glottis ulcer General
symptom
Vague throat Destructive supraglottic lesion. The
Klein et al M 37 pain, lesion was exophytic, extending down Smoking
Weightloss, to the true vocal folds
SOB stridor
Fernández Edema, erythema and leukoplakia of Itraconazole treatment 30 M - Hoarseness Liesa et al the right vocal cord
Yen et al F 46 Dysphonia Epiglottic mass
Yellowish, edematous mucosal
the vocal histoplasmosis 2 months DM
cords
None Amphotericin covered with a thin white exudate.
ative lesion in 2 cases. False cord and pulmonary or systemic
involvement was seen in 3 cases and Itraconazole in 7 cases.
amphotericin
Paranasalsinus followed by itraconazole SLE
pulmonary for 8 months.
Pharyngeal Amphotericin B SLE
oral cavity dead
Itraconazole Oral lesion Endemic (epiglottis and glottis) for 6 weeks
Exophytic lesion was noted on the Itraconazole Oral cavity Endemic anterior aspect of both vocal cords for 6 week
Heptospleno- Amphotericin followed by AIDS megaly Itraconzale for 12 months
the left Amphotericin then Smoking Pharyngeal pyriform sinus and supraglottic space itraconzale Diabetes
Tracheostomy
gastrostomy tube
Pulmonary amphotericin Rheumatoid arthritis patients was
decanulated
Treatment with oral
None ketoconazole was all larynx instituted
Treatment with Oral cavity amphotericin B resulted Endemic TB Pharyngeal in a rapid recovery
Oral cavity Tracheotomy,
Itraconazle for 13 week
None Smoker Travel was successful
Amphotericin then
Disseminated Itraconazole -
death
32 General Coiffier et al M 10 Ulcerated pharyngo-laryngeal lesions Disseminated Endemic symptoms
SOB, 33 Verrcous mass anterior third left vocal Esophagus Itraconazole Postma et al M 54 Globus,
Hoarsness
Oral ulcer
Alcurra et al M 61 Weightloss Multiple laryngeal, glottis ulcer 2 months Smoker
Fever
Samuel et al M 60 Sore throat Supraglottic ulcer 36 Supraglottic, glottic and subglottic Intubated, Rajagobal et al M 72 Dysphonia,
Weightloss
37 Dysphagia, Zain et al M 63 Glottis and Supraglottic mass General,
Symptoms
38 Hoarseness, Wolf et al M 60 Glottic mass Dyspnea
Fever,
César Garcia de Nausea, 39 F 25 Ulcerated mass in the glottis space None died of cardiovascular Alencar et al Weightloss,
Dysphonia, White necrotic lesion spread
Pochini Dysphagia, throughout his larynx, exophytic 40 M 44 Sobrinho et al Sore throat, lesion in the upper right border of the
Weightloss epiglottis
dyspnea) and 36 patients had general symptoms (70%) ( fever,
night sweat and weight loss) Chart 3A.
Seventeen patients had laryngeal histoplasmosis in glottic area,
17 patients had laryngeal histoplasmosis in supraglottic area,
and 2 patients had laryngeal histoplasmosis in subglottic area,
while the other 15 patients had laryngeal histoplasmosis in mul-
tiple laryngeal areas Chart 3B.
Clinical laryngeal exam revealed the presence of a mass
in 22 patients, ulcerated mass in 8 patients, nodule in 4 patients,
granuloma in 4 patients, ulcer in 7 patients, ulcerated mass in 8
patients and other forms (keratosis, thickness and irregularity of
vocal cord, leukoplakia and inflammation) in 6 patients (Chart 4).
Amphotericin B then oral
itraconazole
cord Pharyngeal 1 year
Itraconazole Oral cavity
Esophagus
Pharyngeal Micronazole for 1 month - Pulmonary oral cavity
Pharyngeal Smoker mass 1 year itraconazole
Oral cavity Amphotericin Addison
Disease
Pulmonary Amphotericin -
Amphotericin B patient Larynx
tuberculosis complications
Amphotericin
None B then AIDS
fluconazole
Twenty patients were living in endemic area, 6 patients had his-
tory of travelling to endemic area, 12 patients were smokers, 3
patients had AIDS, 5 patients had a history of Tuberculosis, 3
patients had endocrinology diseases (DM, Addison disease), 4
patients had rheumatology diseases, 2 patients were on immu-
nosuppressant medications and one patient had hepatic cirrhosis
(Table 2).
Eleven patients had histoplasmosis in pharynex (23%), 8 pa-
tients had histoplasmosis in pulmonary tract, 7 patients hadhis-
toplasmosis in oral caviy (17%), 4 patients had hsitoplasmosis
in other organs (9%) (esophagus, nose, liver) and, 6 patients had
disseminated histoplasmosis disease (13%) Chart 5.
Nine patients received only IV amphotericin, 15 patients re-
ceived IV amphotericin followed by itraconazole, and 22 pa-
tients received only azole medications Table 3.
Only 36 articles reported treatment period that vary
from 1 month to 12 months, the treatment should be continued
until the symptoms improve and the physical exam did not re-
Endemic Travel Smoking AIDS TB
20 5 12 3 5
Some patients had multiple risk factors
veal the presence of laryngeal histoplasmosis (Chart 6).
3 patients were dead, while the other 48 patients improved, no
recurrence were reported.
Histoplasmosis is a worldwide distribution granulomatous dis-
ease that is caused Histoplasma capsulatum which is a dimor-
Endocrinology Rheumatology Medications Cirrhosis diseases diseases
3 4 2 1
Amphotericin Azole medications
3 patients had a temporary tracheostomy, 2 patients had temporary gastrostomy tube.3 patients were dead
phic intracellular fungus.1
The fungus usually exists in the mycelial phase at room
temperature. However once the spores are inhaled, the spores
transform to the yeast phase which is responsible for the human
infection and which leads to pulmonary infection that may be
complicated by haematogenous spread to other organs. Primary
pulmonary histoplasmosis is usually asymptomatic but chronic
pulmonary histoplasmosis is clinically similar to pulmonary tu-
berculosis.1
The clinical scenario of ranges from a mild infection
localized to the gastrointestinal tract, skin, larynx or other extra
pulmonary sites to severe disseminated multisystem disease that
involve the bone marrow, liver, spleen and lungs.
The most common clinical presentation of laryngeal
histoplasmosis is secondary to chronic disseminated histoplas-
mosis as a result of haematogenous spread. There are a few re-
ports of sporadic primary laryngeal histoplasmosis cases.
The degree of infection is determined by the size of the
inoculum and prior immune status of the host. It is often associ-
ated with general symptoms such low grade fever, weight loss
and fatigue. Other symptoms of laryngeal histoplasmosis may
include hoarseness, dysphagia, sore throat, cough and occasion-
ally stridor.1
It is known that macrophages are the major targets of
H. capsulatum. The fungal surface heat shock protein 60 (hsp60)
binds to alpha 2 integrins on macrophages surface. So macro-
phages are induced by this binding to secrete Tumor Necrosis
Factor (TNF) which stimulates and recruits other macrophages
to kill the histoplasma.41
Laryngeal involvement is usually observed in dissemi-
nated histoplasmosis. Goodwin et al42 observed that 66% of pa-
tients with chronic pulmonary histoplasmosis and 31% with sub-
Amphotericin+itraconazole Dead
9/51 24/51 15/51 3/51
acute pulmonary histoplasmosis developed laryngeal disease.
Involvement of the larynx was observed in only 19% of patients
with acute disseminated histoplasmosis.43
Chest radiography, sputum and urine cultures and bone
marrow aspiration biopsy should be done in any laryngeal histo-
plasmosis case to look for disseminated disease.39
Clinical presentations of the laryngeal histoplasmosis
include granulomas, ulceration, nodular ulcerative lesions, and
verrucous and plaque-like lesions.39
Histoplasmosis affects 4% to 5% of patients with AIDS,
on whom it generally causes acute or subacute clinical disease
with disseminated illness. These presentations of the infection
takes place in patients with CD4 T-cell counts lower than 200
cells/μl.39
In the biopsy, it can be observed with hematoxylin-eo-
sin granulomatous tissue, necrosis, and infiltration of giant cells,
lymphocytes, plasma cells and many macrophages. By using
special stains such as coloring Gomorimethenamine-silver, col-
oring periodic acid-schiff (PAS) staining or Gridley technique40
to identify macrophages and these cell containing hyphae.
Macroscopically, histoplasmosisshouldbe differentiat-
ed from syphilis, tuberculosis, carcinoma, mid-line granuloma,
mucormycosis, lymphoma,and other granulomatous diseases.40
Anti-histoplasma serological tests using complement
fixation and immune-diffusion methods are positive in about
90% of immune-competent patients and 70% of immune-
compromised patients. Antibody tests may be false negative in
immune-compromised patients. The antibodies usually start to
appear during the second month after exposure in acute phase,
and they may remain positive for several years.44
The treatment of laryngeal histoplasmosis is similar to
the other forms of the disease. Although it is usually benign,
histoplasmosis can be disseminated and cause severe fatal dis-
ease. Treatment of choice is IV amphotericin B, 0.3-0.6 mg/kg
of body weight per day, with a maximum dose of 2-4 mg. Muco-
sal laryngeal lesions respond within 6-8 weeks, recurrences may
occur. Itraconazole is an alternative treatment for laryngeal his-
toplasmosis. It is given orally 100 mg daily until clinical cures
is achieved and then change the treatment regimen to 50 mg/day
for 6 more months.44
Laryngeal histoplasmosis is more common in male, most pa-
tients are over 40 year old and native or have a history of travel-
ing to endemic area. It is usually associated with pharyngeal or
pulmonary involvement. There is no specific laryngeal location
for it, hoarseness is the most common symptom and mass (non-
ulcerated or ulcerated) is the most common clinical finding dur-
ing laryngeal exam. Treatment is by amphotericin, itraconzale
or both. Some patients may need tracheostomy to relieve acute
respiratory obstruction or gastrostomy tube for feeding. Progno-
sis is usually good with a few fatal cases in disseminated disease.
The authors wish to acknowledge John Cotton Dana Library, NJ,
USA, for their kind help to get the reference papers.
The author declare that he have no conflicts of interest.