CHAPTER SIXTY-FOUR
Laryngeal and Tracheal
Manifestations of Systemic
Disease
Kevin P. Leahy
Key Points
• The spectrum of laryngeal and tracheal symptoms of systemic disorders can vary from mild to severe, including hoarseness, cough,
stridor, and airway compromise.
• Many systemic disorders that affect the larynx may mimic laryngeal carcinoma.
• A systemic process should be suspected in a hoarse patient with no obvious lesion.
• Many systemic disorders require a multidisciplinary approach to achieve optimal results, involving a speech pathologist,
rheumatologist, infectious disease specialist, and otolaryngologist.
The number of problems that can affect the larynx and trachea are
protean. Their manifestations can range from mild hoarseness to airway
obstruction. Thankfully, most manifest as the former. In evaluation of
a patient with a laryngeal or tracheal complaint, the problem may be
classified as either malignant or nonmalignant. However, this is not
accomplished so easily, because many nonmalignant processes can
mimic malignancy, at least prior to biopsy. It is therefore up to the
otolaryngologist to remain suspicious and think on a broader scale.
Such an approach requires that a basic understanding of the variety of
disease states that affect the larynx is an integral part of the otolaryn-
gologist’s armamentarium.
This chapter focuses on nonmalignant diseases that affect the
larynx and trachea. Many of the infectious processes otolaryngologists
encounter, especially those affecting the pediatric population, are
covered in other chapters. This chapter provides a summary of the
many systemic and infectious diseases that can manifest as laryngeal
and tracheal dysfunction and describes their etiology, diagnosis, and
treatment.
Wegener’s Granulomatosis
Wegener’s granulomatosis is a multisystem inflammatory disease char-
acterized by necrotizing granulomatosis and necrotizing vasculitis of
small arteries, arterioles, capillaries, and venules.1,2 It primarily involves
the upper and lower respiratory tracts, including the larynx and trachea,
and kidneys.1 Other areas of involvement are the oral cavity, skin, joints
(polyarteritis), and orbit.1 In the airway, the subglottis and trachea are
more commonly affected (Fig. 64-1).
Airway involvement usually occurs in the presence of systemic
disease but may be the only sign of the illness. Specifically, 10% to
20% of patients with Wegener’s granulomatosis present with subglottic
involvement and subsequent stenosis.1,3,4 As a result, patients may be
incorrectly diagnosed as having asthma when stridor is mistaken for
wheezing. Glottic involvement manifests as voice changes. Most
patients with Wegener’s granulomatosis have a positive ANCA
(antineutrophil cytoplasm antibody) test result, but up to 20% of
patients who have the disease with respiratory involvement have nega-
tive ANCA test results.2
Common symptoms of Wegener’s granulomatosis of the airway
include hoarseness, cough, hemoptysis, dyspnea, stridor, and wheezing.
Progressive respiratory difficulty with stridor can be the first signal of
airway involvement. Pulmonary function testing with flow-volume
loops can be helpful in distinguishing a fixed extrathoracic lesion (i.e.,
subglottic stenosis) from parenchymal disease.2 The typical pattern of
flattening of both inspiratory and expiratory phases is seen in fixed
lesions.2
Management of the disease is complex and usually requires a
multidisciplinary approach. Systemic manifestations are treated with
systemic corticosteroids and other immunomodulating agents, depend-
ing on disease severity. First-line treatment is with steroids plus cyclo-
phosphamide.2,4 Once remission has been achieved, methotrexate or
azathioprine is used.2 Airway disease in Wegener’s granulomatosis
presents a complex challenge because it frequently behaves independ-
ently of the systemic disease. Treatment should be tailored to the
presenting symptoms and level of distress.
In the presence of acute airway obstruction, tracheostomy place-
ment can be lifesaving. With current endoscopic techniques, however,
many patients can be managed without tracheostomy.3-5 Although tech-
niques differ, dilation of the stenosis with injection of intralesional
steroids is the mainstay of treatment. There are reports of the use of
topical mitomycin C after dilation.6 Depending on the severity of
narrowing or the level of the stenosis, dilation can be achieved with
rigid dilators or balloon dilation.2-4 The carbon dioxide laser has
also been used to treat subglottic stenosis.6 In patients with difficult
stenoses, stents or tracheostomy can be used. Finally, resection and
890 Part 5 n Laryngology and Bronchoesophagology
Figure 64-1.  Active Wegener’s granulomatosis. Yellow crusting and
subglottic narrowing can be seen.
reanastomosis have been used to remove the stenotic segment, but this
step is usually reserved for mature stenoses and inactive disease.
Relapsing Polychondritis
Relapsing polychondritis is a rare inflammatory disease of unknown
etiology that causes episodic inflammation of cartilaginous structures
throughout the body.7 Commonly affected areas are the ears, nose, eyes,
larynx, bronchi, costal cartilages, and articular joints. Males and females
are affected equally, with an annual incidence of 3.5 per million.8 All
ages can be affected, but peak onset is somewhere in the fourth to fifth
decade. Only about 14% of patients present with airway symptoms,
but 50% to 55% of patients eventually have them.7 Diagnosis is based
on the presence of multiple criteria, first described by McAdam and
colleagues7 and later modified by Damiani and Levine.9 The most
common finding is bilateral auricle chondritis. Respiratory involvement
is less common but more damaging. In 25% to 35% of patients with
relapsing polychondritis there is a preceding autoimmune process.8,10
Involvement of the respiratory tract can have serious conse-
quences. Typically patients present with hoarseness, cough, choking,
wheezing, dyspnea on exertion, stridor, or tenderness of the laryngeal
framework.7-9 Mortality rates are reported anywhere from 10% to 50%
when the laryngotracheobronchial tree is involved.8 The airway can be
involved at various levels, making treatment difficult. Upper airway
obstruction can occur with laryngeal involvement. Collapse of the
trachea or bronchi happens when the more distal airway is affected.
Respiratory distress may occur by either of two mechanisms, collapse
of the central airway from destruction and fibrosis of the laryngeal and
tracheal cartilages or peripheral airway narrowing from inflammation
and cicatricial fibrosis.11 Patients may ultimately require tracheostomy
for airway stabilization.
Imaging can be helpful in the diagnosis of relapsing polychondri-
tis. Plain films can demonstrate the nonerosive arthropathy seen in the
disease.9 Airway fluoroscopy has been implemented to evaluate for
central airway collapse during expiration.11 Magnetic resonance imaging
and computed tomography are complementary in the diagnosis of
relapsing polychondritis. Typical computed tomography findings
include subglottic stenosis, tracheobronchial luminal narrowing, dense
calcification and thickening of tracheal cartilages, peripheral bronchial
narrowing, and bronchiectasis11; the most common finding is increased
attenuation and smooth thickening of the airway walls.11 Magnetic
resonance imaging is very sensitive for visualization of soft tissue inflam-
Figure 64-2.  Laryngeal sarcoidosis. Note the hyoepiglottic ligament
and the prominence of the hyoid bone. The epiglottis has its classic
appearance, nodular and “turban-like.”
mation. Such inflammation tends to be hyperintense on T2-weighted
images, and to enhance with gadolinium on T1-weighted images.8
Histologic examination shows chondritis with a mixed inflamma-
tory cell infiltrate composed of polymorphonuclear leukocytes, lym-
phocytes, plasma cells, and eosinophils, depending on the stage at
which the lesion is sampled.7,9 The primary change is the loss of matrix
mucopolysaccharides followed by a secondary perichondrial inflamma-
tory reaction.12
In addition to surgical measures, relapsing polychondritis is
managed with high-dose corticosteroids. Maintenance therapy consists
of methotrexate and low-dose corticosteroids. Azathioprine, cyclophos-
phamide, cyclosporine, and dapsone have been tried in refractory cases.8
There have also been case reports of the use of infliximab, which blocks
tumor necrosis factor α, to treat refractory cases.13
Sarcoidosis
Sarcoidosis is a chronic granulomatous disease of unknown etiology. It
is characterized by noncaseating granuloma formation with clusters of
tubercles in the same stage of development.14,15 It can affect any organ
system within the body.14 Nine percent of all patients with sarcoidosis
have head and neck manifestations.14 The first histopathologic diagno-
sis of laryngeal involvement was confirmed by Poe in 1940, despite its
earlier description in the literature.14,15 The estimated incidence of
laryngeal sarcoidosis is between 1% and 5%.14 Although rare, laryngeal
sarcoidosis can be the only manifestation of the disease.
Symptoms are generally mild despite extensive tissue involvement.
The progression of the disease is slow and is characterized by many
relapses and remissions.15 With respect to laryngeal involvement, symp-
toms typically include hoarseness, dyspnea, stridor, dysphagia, and
cough.14,16,17 However, patients can be asymptomatic. Rarely, airway
obstruction may be the presenting symptom.14
The supraglottic larynx is affected most often, followed by the
subglottis. The vocal folds are frequently spared. The epiglottis is the
most common subsite, followed by the arytenoids, aryepiglottic folds,
and false vocal folds.14 When airway involvement is suspected, laryn-
goscopy is a key step in the diagnosis.
The classic appearance of the larynx affected by sarcoidosis is
described as “turban-like thickening” (Fig. 64-2).15 This thickening is
due to the pale, pink, diffuse induration and swelling of the supraglot-
tis. Flexible fiberoptic examination may reveal the presence of edema
and erythema, punctate nodules, mass lesions, and ulcerations.14 Biopsy
of affected areas shows lymphocytic infiltration and noncaseating epi-
thelioid granulomas.14 The pathologic findings can be confused with
those in other granulomatous diseases, and additional studies and cul-
tures are recommended.14
 Chapter 64 n Laryngeal and Tracheal Manifestations of Systemic Disease
Figure 64-3.  Laryngeal amyloid deposition in the supraglottis (right
ventricular fold, laryngeal surface of epiglottis) and sparing of the true
vocal folds. The patient presented with hoarseness and a nonproduc-
tive cough.
Treatment of the laryngeal manifestations of sarcoidosis can be
achieved with systemic corticosteroids. For lesions that are small and
well circumscribed, some writers have performed intralesional injection
of corticosteroids.14,17 In cases in which there is airway obstruction,
excision with the carbon dioxide laser or Microdebrider can be per-
formed to prevent the need for a tracheostomy. It is preferable to treat
lesions when they are nonobstructing so as to avoid the need for a
tracheostomy.17 Due to the risk of laryngeal involvement, it is recom-
mended that patients with sarcoidosis who begin to have airway symp-
toms be evaluated by an otolaryngologist.15
Amyloidosis
Amyloidosis is an idiopathic disorder characterized by the extracellular
deposition of insoluble fibrillar proteins. Interestingly, the origins of
these fibrillar proteins are their normally soluble variants. These depos-
its were initially described by Rokitansky in 1842.18 The first laryngeal
case was described by Borow in 1873.18 Since then it has rarely been
described as affecting the larynx, accounting for as little as 0.2% of
benign tumors of the larynx.19 However, laryngeal deposition of
amyloid is the most common involvement within the head and neck.18
Other deposits can occur anywhere in the upper and lower aerodigestive
tract.
Amyloidosis is classified on the basis of the following three
parameters: the fibrillar protein making up the deposits, the precursor
protein from which the amyloid protein was derived, and the clinical
description of the associated disease process (primary, secondary, mye-
loma-associated, familial, or hemodialysis-associated amyloidosis).18
Laryngeal amyloidosis is usually a localized and primary disease but
may be found in association with an underlying disorder, such as mul-
tiple myeloma.18
Presenting symptoms vary with the amyloid deposition. The most
common location within the larynx is deposition in the true and false
vocal folds and the ventricles (Fig. 64-3).20 Frequently complaints
revolve around hoarseness or cough, but if deposition is significant,
dyspnea or stridor may also be seen.
Biopsy of the primary lesion is the mainstay of diagnosis. On light
microscopy, amyloid exhibits an acellular, amorphous, homogeneous,
eosinophilic appearance after hematoxylin and eosin staining.18 The
classic findings of bright green birefringence under polarizing light
microscopy are seen after staining with Congo red. Other diagnostic
tests that should be performed are complete blood count, liver function
tests, renal function studies, and urinalysis to look for the Bence-Jones
protein.18 A referral to a hematologist or oncologist is appropriate, given
the association of amyloidosis with multiple myeloma.
891
Figure 64-4.  This patient was known to have rheumatoid arthritis. She
experienced hoarseness, and fiberoptic examination showed bilateral
midfold thickening.
Treatment is focused on maintaining airway patency and improv-
ing hoarseness while minimizing the effects on voice quality.18,20 The
treatment is routinely performed during suspension microlaryngoscopy
with excision. Microdebrider excision and carbon dioxide laser excision
are two modalities currently employed. Recurrence of amyloid deposits is
common and is managed with reexcision. Rarely, tracheostomy is needed.
Rheumatoid Arthritis
Rheumatoid arthritis is a common autoimmune disease that involves
inflammation of the synovial tissue.21 Women are two to three times
more likely to have the disease. The larynx is involved in 25% to 30%
of cases. The symptoms vary from hoarseness and dysphagia to globus
sensation and even stridor.22
Rheumatoid arthritis affects the larynx in two forms. In the active
form, there is acute involvement of the larynx with tenderness and
erythema. Laryngoscopic examination often shows red, swollen aryte-
noids.23 The chronic form typically causes cricoarytenoid joint involve-
ment with ankylosis.23 This can result in bilateral impairment of vocal
fold motion requiring urgent intervention, with both medical and
surgical treatments.24,25
In addition to joint involvement, submucosal nodules can develop
on the vocal fold (Fig. 64-4). Their histologic appearance is similar to
that of rheumatoid nodules found elsewhere in the body. Most often,
these nodules lead to hoarseness, and when removed, the voice quality
improves.22 There have been case reports of patients treated with meth-
otrexate in whom giant rheumatoid nodules developed within the
larynx, causing airway obstruction.21,23
Pemphigus
Pemphigus is a rare autoimmune disease that affects the skin and
mucous membranes. The loosening of the epidermal-dermal junction
leads to the characteristic formation of blebs. The disease is most com-
monly encountered by dermatologists; however, in the experience of
Hale and Bystryn,26 laryngeal complaints were not uncommon when
nasal complaints were also present. Pemphigus may be isolated to the
larynx, but this is unusual.27 Most often, precedent nasal or oral lesions
are found. The most common laryngeal presentation of this disease is
hoarseness, although progressive stridor and dyspnea may be the pre-
senting symptoms.28 On fiberoptic examination, one will typically see
supraglottic involvement affecting the laryngeal surface of the epiglottis,
892 Part 5 n Laryngology and Bronchoesophagology
Figure 64-5.  Progressive dyspnea. The fibrinous exudate is classic for
pemphigus. Bullae typically are not seen in the upper aerodigestive
tract because they rupture and slough off, leaving behind the fibrinous
exudate as seen here.
aryepiglottic folds, and the arytenoid mucosa. The lesions that are
encountered do not have the typical bleb appearance because the epi-
dermis is sloughed off by swallowing. What is left is a tan fibrinous
base with a halo of erythema (Fig. 64-5).28,29 If this condition is encoun-
tered, a thorough inspection of the oral cavity mucosa (most common
site in the head and neck)27 and nasal cavity may reveal other lesions.26
Because of the underlying inflammatory response, scarring can be
prevalent and can lead to supraglottic narrowing.
Diagnosis relies on tissue biopsy. Because of the fragile nature of
the mucous membranes, care should be taken in the performance of
endoscopy. The classic histologic finding is intraepithelial acantholy-
sis.28,29 Pemphigus typically has acantholytic lesions that are subepithe-
lial with basement membrane involvement. Direct immunofluorescence
in pemphigus has an intracellular pattern. Indirect immunofluores-
cence can measure the amount of circulating antibodies and correlates
with disease severity.27
Treatment is based on oral corticosteroids. High doses are given
at first and are then tapered to a maintenance regimen. Azathioprine,
cyclophosphamide, and cyclosporine have been used as maintenance
medications for pemphigus.27,28
Whooping Cough
Whooping cough, caused by Bordetella pertussis, has been increasing in
frequency in the United States.30 Originally a disease of childhood, it
is now more commonly seen in infants, adolescents, and adults. The
reason for this increase is unknown. It is believed that despite vaccina-
tion, the maximum protection is conferred for 3 years, with decreasing
effectiveness each year thereafter.31
Adults who become infected do not typically experience the
catarrhal stage with fever and leukocytosis,32 but instead have a severe
protracted cough. Treatment with antibiotics, typically erythromycin,
does not change the clinical course but does prevent transmission.30
Azithromycin has also been found helpful in prophylaxis.
Tuberculosis
Over the years, the clinical presentation of laryngeal tuberculosis has
changed. Usually laryngeal tuberculosis developed in the presence of
severe pulmonary tuberculosis, secondary to expectorated secretions
containing the organism.33 Most patients who present today are without
pulmonary symptoms or a history of pulmonary tuberculosis. It is
theorized that laryngeal disease is the result of hematogenous or lym-
phatic spread.34,35 Despite these changes, the most common presenting
symptom is hoarseness.34-36 Other symptoms are dysphagia, odynophagia,
cough, and weight loss.34,36 Despite the lack of pulmonary involvement,
the purified protein derivative test result is usually positive.37,38
The location within the larynx has also changed with time. The
most common location was the posterior glottis. It has been supplanted
in frequency by various other subsites of the larynx: vocal folds, ven-
tricular folds, aryepiglottic folds, as well as the posterior glottis.33,36 The
lesions may be nodular, exophytic, or ulcerative.33,36-38 Because of the
appearance of the lesions, laryngeal tuberculosis can be mistaken for
squamous cell carcinoma.36
Diagnosis is usually made by the combination of sputum culture,
biopsy specimens testing positive for acid-fast bacilli, and chest radio-
graphs.36 Medical therapy can alleviate symptoms and expedite the
improvement in hoarseness. During the workup for laryngeal tubercu-
losis, patients should be screened for human immunodeficiency virus,
given the high incidence of co-infection with the two pathogens.
Histoplasmosis
Histoplasmosis is caused by the dimorphic fungus Histoplasma capsu-
latum.39,40 Endemic regions in the United States include the Ohio and
Mississippi river valleys. Infection varies according to the initial expo-
sure. It may manifest as either an acute or chronic pulmonary infection
or an acute or chronic disseminated infection with systemic symp-
toms.40 Both of the pulmonary processes are usually self-limited, unless
concomitant immunosuppression is present (i.e., due to human immu-
nodeficiency virus).39,40 Acute disseminated histoplasmosis is almost
always fatal.41 Chronic disseminated disease usually manifests as focally
destructive lesions.39,40
Mucosal involvement is common and can resemble lesions of
squamous cell carcinoma or tuberculosis.42-44 Biopsies can show the
presence of poorly defined granulomas with macrophages and multi-
nucleated giant cells.40,42 Periodic acid–Schiff and Grocott stains can
show intracellular H. capsulatum.42-44 These ulcers begin as flat, plaque-
like, nontender elevations that become painful after ulceration.43 Treat-
ment is with intravenous amphotericin B.
Blastomycosis
The organism responsible for blastomycosis is the dimorphic fungus
Blastomyces dermatitidis. This soil saprophyte can be found throughout
the United States and Canada but is endemic along the Mississippi and
Ohio river basins. The primary portal of entry is through the lungs.39
Hematogenous spread accounts for other organ involvement. Skin is
the most commonly affected system, in contrast to the larynx, which
can be involved in about 2% of cases.39,45 Prior to antifungal therapy,
the mortality of blastomycosis exceeded 60%.39
Laryngeal involvement typically leads to hoarseness as the chief
complaint.45,46 Examination typically reveals exophytic masses, but
ulcerative lesions have been described. The true vocal folds are the most
common subsite, with extension to the ventricular folds. Because these
lesions can be mistaken for squamous cell carcinoma, biopsy is critical
for diagnosis.
The typical histologic findings include acute and chronic inflam-
mation, microabscesses, and giant cell formation. The hallmark finding
is pseudoepitheliomatous hyperplasia.39 Fungal stains (e.g., Gomori
methenamine silver) show the organism as a double-walled sphere 8
to 15 mm in diameter with single broad-based buds.39 In addition
to histologic identification, culture of the organism is performed in
enriched agar medium. For uncomplicated cases, prolonged oral keto-
conazole or itraconazole treatment can be given. Amphotericin B is also
effective, especially in cases with central nervous system involvement.
Cryptococcosis
Cryptococcosis is a systemic infection caused by Cryptococcus neoform-
ans, a yeastlike fungus with a thick polysaccharide capsule.39 It is found
in areas contaminated with pigeon droppings.39 As in blastomycosis,
infection is through inhalation of the spores. The pulmonary disease in
nonimmunocompromised patients is generally subclinical. However, in
 Chapter 64 n Laryngeal and Tracheal Manifestations of Systemic Disease
immunocompromised patients, systemic involvement is typical. The
most commonly affected system is the central nervous system, leading
to meningitis. Most cases of laryngeal involvement occur in immuno-
compromised patients, but there are rare cases in immunocompetent
patients.39,47 The true vocal folds are the only site affected, with subse-
quent hoarseness. On biopsy, budding yeast can be seen. As seen in
blastomycosis, pseudoepitheliomatous hyperplasia may be identified.
Depending on the severity of the infection, treatment involves ampho-
tericin B or fluconazole.39,47
Coccidioidomycosis
Coccidioides immitis, the fungal organism responsible for San Joaquin
Valley fever, is endemic to the southwestern United States and north-
ern Mexico.39 Spores are inhaled, and 60% of infections go unrecog-
nized. In the remaining 40%, flulike symptoms occur 1 to 3 weeks after
infection.39 Most cases of laryngeal involvement occur in disseminated
coccidioidomycosis. Symptoms range from hoarseness, pain, and
odynophagia to airway involvement with stridor.48,49 Amphotericin B
is the mainstay of treatment.
Actinomycosis
Actinomycosis is a chronic suppurative infection characterized by the
presence of purulent drainage from chronic discharging sinus tracts
containing the pathognomonic sulfur granules.39 The causative organ-
ism is Actinomyces israelii, an anaerobic or microaerophilic, non–acid-
fast, gram-positive organism. These organisms are endogenous to the
oral cavity and can be found in carious teeth, plaque, and tonsillar
crypts.39 Cervicofacial actinomycosis accounts for 50% to 60% of all
cases.39 Laryngeal and tracheal cases have been reported.50 Treatment
involves prolonged antibiotic therapy; the mainstay is penicillin,
although clindamycin has also been used.39,50
Candidiasis
Candidiasis affecting the larynx tends to be associated with oral and
esophageal involvement as well. Affected patients are typically immu-
893
nocompromised owing to chemotherapy or acquired immunodefi-
ciency syndrome. Isolated laryngeal candidiasis has been seen, especially
in patients using inhaled corticosteroids.51-53 The lesions are usually
white sessile plaques on an erythematous base; however, ulceration may
be noted.51 Therapy is focused on eliminating the causative agent (i.e.,
steroid inhaler) and the addition of an oral antifungal agent, such as
fluconazole.51,53 Also, candidal overgrowth is associated with failure of
a tracheoesophageal puncture voice prosthesis.
SUGGESTED READINGS
Damiani JM, Levine HL. Relapsing polychondritis—report of ten cases. Laryn-
goscope. 1979;89:929-946.
Ellison DE, Canalis RF. Sarcoidosis of the head and neck. Clin Dermatol.
1986;4:136-142.
Hale EK, Bystryn JC. Laryngeal and nasal involvement in pemphigus vulgaris.
J Am Acad Dermatol. 2001;44:609-611.
McAdam LP, O’Hanlan MA, Bluestone R, et al. Relapsing polychondritis:
prospective study of 23 patients and a review of the literature. Medicine
(Baltimore). 1976;55:193-215.
Polychronopoulos VS, Prakash UB, Golbin JM, et al. Airway involvement in
Wegener’s granulomatosis. Rheum Dis Clin North Am. 2007;33(VI):755-
775.
Pribitkin E, Friedman O, O’Hara B, et al. Amyloidosis of the upper aerodiges-
tive tract. Laryngoscope. 2003;113:2095-2101.
Vrabec DP. Fungal infections of the larynx. Otolaryngol Clin North Am.
1993;26:1091-1114.
Woo P, Mendelsohn J, Humphrey D. Rheumatoid nodules of the larynx.
Otolaryngol Head Neck Surg. 1995;113:147-150.
For complete list of references log onto www.expertconsult.com.