Nonsquamous Pathologic Diseases of the Hypopharynx, Larynx, and Trachea

Clinical Features

Initial symptoms of laryngeal tuberculosis include hoarseness, cough, hemoptysis, and dysphagia. The mode of spread to the larynx and trachea is still mostly through expectorated sputum. Although the association of laryngeal tuberculosis with advanced cavitary pulmonary disease is uncommon, most patients with laryngeal tuberculosis also have bacilli in their sputum, still favoring direct pulmonary spread rather than hematogenous seeding. Laryngeal lesions may be nodular and ulcerated, clinically mimicking carcinoma. Seventy percent of these lesions affect the anterior two-thirds of the vocal cords, similar to the distribution of most vocal cord carcinomas. This is in contrast to former tenets that MTB mainly affected the posterior interarytenoid area. This posterior commissure predisposition for infection, documented in the older literature, most likely was related to the clinical practice of encouraging patients to lie supine for most of their illness.

Pathologic Features

The usual histology of late infection is that of necrotizing granulomas, epithelioid histiocytes, giant cells, and lymphoplasmacytic infiltrates ( Fig. 5.5 ). Early infection may be histologically nonspecific, with an acute inflammatory infiltrate and a lack of well-formed granulomas. The diagnosis of tuberculosis requires a Ziehl-Neelsen stain and patience, as one might have to examine many step sections to find a solitary “red snapper.” Modified Dieterle’s stain will also stain MTB; the acid-fast bacilli do not stain with hematoxylin and eosin or Gram stain.

Special Studies

If laryngeal MTB is suspected (based on the presence of a pulmonary lesion and/or positive sputum or a strongly positive skin reaction) and the biopsy sample fails to reveal acid-fast bacilli, one can also submit fresh or formalin-fixed, paraffin-embedded tissue for polymerase chain reaction analysis.

Differential Diagnosis

Normal laryngeal mucosa rarely harbors significant inflammation; therefore any moderate to severe acute and/or chronic inflammation should be viewed as pathologic, and the possibility of infection should be considered. Apart from tuberculosis, granulomatous inflammation in the larynx can be seen in some other rare infections, such as in coccidiodomycosis, cryptococcosis, blastomycosis, and leprosy. Tuberculoid leprosy can be distinguished from tuberculosis as leprosy may involve nerves, which is uncommon for tuberculosis, and M. leprae will not stain with a Ziehl-Neelsen stain, but will stain with a Fite-Faracco stain.

An important differential diagnosis is sarcoidosis. Granulomata in sarcoidosis are characteristically nonnecrotizing, although, rarely, necrosis may be present. Special studies (e.g., cultures, special stains, polymerase chain reaction) and clinical examination are necessary to exclude the diagnosis of tuberculosis.

Laryngeal tuberculosis must be distinguished from foreign body–type granulomatous inflammation in the larynx, which can be seen after Teflon injection or with laryngeal amyloidosis. Granulomas are also an important feature of Wegener’s granulomatosis (granulomatosis with polyangiitis). In the latter, the presence of vasculitis is helpful, as well as the presence of antineutrophil cytoplasmic antibodies in the serum (ANCA).

Treatment

Empirical therapy (isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol) is recommended for 8 weeks followed by isoniazid and rifampin for 16 weeks for susceptible strains. Multiple drug–resistant MTB requires these four drugs, plus any three of the following: ethionamide, capreomycin, ciprofloxacin, or cycloserine. The course of therapy may need to be lengthened if the patient’s sputum remains positive after 3 months.

Clinical Features

Leprosy has a predisposition to affect cooler peripheral areas, such as the digits, ears, and nose. It presents as cutaneous hypo- or hyperpigmented, hypoesthetic isolated macular lesions. Early lesions may also be tender, erythematous, and indurated (erythema nodosum leprosum) and can ulcerate. Neural involvement is common to all types of leprosy and results in severe pain and muscle atrophy. Sensory loss ultimately leads to repeat mechanical trauma and secondary infections.

Lepromatous leprosy presents with widespread symmetric facial distribution of lesions leading to coarsening of features (leonine facies). The earlobes and nose are especially enlarged and infiltrated. Intranasal and paranasal sinus involvement is common and occurs after cutaneous nasal involvement. Paranasal sinus involvement causes mucopurulent rhinitis, producing copious mucus rife with mycobacteria. Early mucosal lesions are plaque-like; late sinonasal lesions are nodular and/or ulcerative and may ultimately lead to nasal collapse.

The larynx usually becomes infected retrograde to the nasal disease. In a study of 973 untreated leprous patients, laryngeal involvement was related to mycobacterial load: it was seen in 65% of patients with lepromatous leprosy and was usually seen with the most advanced cases. The epiglottis was most often involved, appearing thickened and irregular, probably mirroring the predisposition of M. leprae for cooler sites. Vocal cord paralysis, secondary to recurrent laryngeal nerve involvement, was present in 9% of patients. Upper airway obstruction and dysphonia have been reported as a consequence of laryngeal leprosy.

Pathologic Features

Tuberculoid leprosy (TL) reveals epithelioid granulomas and relatively few organisms, seen only on Fite-Faraco or modified Fite stain. Nerves are surrounded by cuffs of lymphocytes or granulomas or may contain free acid-fast bacilli. Lepromatous leprosy is characterized by a poor immunologic response and reveals diffuse infiltration by histiocytes that are incapable of undergoing epithelioid transformation and unable to form granulomas. These foamy histiocytes (lepra cells, Virchow cells) may be “stuffed” with abundant mycobacilli (globi), which remain uncleared by the host. Free bacilli may also be abundant within nerves. Between these two extremes, there are borderline cases (i.e., borderline tuberculoid and borderline lepromatous), with variable immunologic response (i.e., mixture of ill-formed granulomas and foamy histiocytes). The histoid form of leprosy seen in late leprosy is characterized by spindle-shaped histiocytes forming dermatofibroma-like tumors, similar to spindled pseudotumors that can develop in atypical mycobacterial infections.

The diagnosis of leprosy is more difficult to establish early in the disease course when mycobacilli may be sparse and granulomas may not be fully developed. Mycobacteria may be sparse or absent in TL. In a biopsy study of 30 cases of laryngeal leprosy, only seven revealed bacilli, most often in cases with foamy histiocytes.

Differential Diagnosis

The differential diagnosis for TL includes mycobacterium tuberculosis (MTB) infection. However, the clinical history should be helpful in ruling out MTB and atypical mycobacteria and in establishing the diagnosis of leprosy. Perineural involvement by lymphocytes, granulomas, or free organisms, an important diagnostic feature of leprosy, is not seen with MTB infections. An acute suppurative reaction is lacking, except for erythema nodosum leprosum, and is present in cutaneous manifestations of MTB. The Fite-Faraco stain is specific for M. leprae and is not known to stain other mycobacteria.

Polymerase chain reaction has been applied to the detection of M. leprae , extracted from formalin-fixed, paraffin-embedded tissue, with excellent sensitivity and specificity.

Treatment

Tuberculoid leprosy may be treated with dapsone and rifampin. Lepromatous leprosy requires the addition of a third agent, such as clofazamine.

Clinical Features

Primary syphilis results in a localized chancre at the mucosal inoculation site, 1 week to 3 months after initial exposure. In addition to genitourinary sites, chancres can develop in the oral cavity after oral-genital contact and may incidentally infect the unwary ungloved examiner. Affected oral sites include the lips, palate, gingiva, tongue, and tonsil. Laryngeal chancres have been reported. Typically, cutaneous chancres are painless, hard, raised lesions that develop shallow ulcerations with sharp raised borders. On mucosal surfaces, primary chancres may appear as silvery gray erosions, granulation tissue, or nonspecific ulcers, or even mimic carcinoma. Chancres are self-healing with minimal scarring.

Secondary syphilis occurs weeks to months after the primary chancre and is the result of hematogenous spirochete dissemination. Epithelial surfaces are frequently involved with a wide manifestation of cutaneous and mucosal lesions. The mucosal lesions include mucous patches, which are raised and flattened, macerated lesions with a thin grayish membranous covering, and painless ulcers resembling aphthous ulcers, macular/papular lesions, and condyloma latum. Patients usually develop fever, pharyngitis, and a generalized, symmetric macular/papular skin rash; the latter may affect the hair follicles of the scalp, eyebrows, and beard, causing a patchy “moth-eaten” alopecia (alopecia syphilitica). The diffuse maculopapular rash can extend intraorally and may be associated with laryngeal hyperemia. The macular/papular lesions coalesce in warm moist areas, such as the anogenital and intertriginous areas, to form the hyperplastic lesion condyloma latum (flat condyloma), which may be infectious. Mucous patches can be seen intraorally and may also be seen on the epiglottis. Condyloma latum may occur in the larynx, ears, and nasolabial folds. Generalized lymphadenopathy occurs during the secondary stage, with a predisposition for periarticular lymph nodes, as in epitrochlear and inguinal areas. Secondary syphilis will lapse into a latent state, but patients may frequently experience recurrent mucocutaneous symptoms of secondary syphilis. When untreated, approximately one-fourth of patients will develop a relapse of secondary symptoms; 90% of relapses occur in the first year of infection. During the early latent phase, patients are still contagious. Tertiary syphilis is the long-term chronic systemic result of untreated infection, which may be manifested years to decades after primary infection. Tertiary syphilis has a predisposition to affect the central and peripheral nervous systems and the cardiovascular system. Gummas, the destructive lesions of late tertiary syphilis, have a proclivity for membranous bones, commonly affecting the palate. Laryngeal framework, nasal and temporal bones, and ossicles may also develop gummas. Gummas are painless raised ulcerative masses that may rapidly progress to necrotic destructive masses. Laryngeal gummas may cause subglottic stenosis and arytenoid fixation. Chondritis/perichondritis may involve the epiglottis and cricoarytenoid joint. Recurrent laryngeal nerve paralysis may occur with meningovascular syphilis and cranial nerve dysfunction or with a cardiovascular syphilitic aortic aneurysm, which may compress the recurrent laryngeal nerve. The oral cavity is commonly affected in congenital syphilis. Mucosal patches on the tongue, palate, and lips may become fissured and hemorrhagic, resulting in radial scars. These children can also develop gummas anywhere within the aerodigestive tract.

Pathologic Features

Nonspecific lymphoplasmacytic infiltrates may be seen in all stages of syphilis. Primary chancre reveals central necrotic debris and dense chronic inflammation at the periphery. Dark-field examination of the chancre demonstrates numerous spirochetes. The overlying epidermis is thinned and ulcerates. Lymphoplasmacytic vasculitis in a “coat sleeve”–like arrangement, giant cells, and endothelial swelling are seen. The Steiner modification of Warthin-Starry silver or Dieterle’s stain will reveal the spirochetes, especially around vessels, which may be seen in the squamous mucosa or submucosa (see Fig. 5.6 ). Interpretation of the silver stains is made difficult by the presence of melanocytes and reticulin fibers, as well as spirochetes other than T. pallidum.

Secondary syphilis is characterized by dense lymphoplasmacytic infiltrates. Granulomas with multinucleated giant cells and epithelioid histiocytes may be a late finding. Spirochetes may be seen in the secondary lesions predominantly around vessels. Vascular endothelial proliferation is more likely to be seen in older lesions. Condyloma latum is composed of epithelial hyperplasia (rather than the attenuated epithelium of chancres) with elongated rete pegs and dense lymphoplasmacytic infiltrates with perivascular cuffing of plasma cells. Lymph nodes contain noncaseating granulomas, perivascular cuffing of plasmacytes, and capsular fibrosis. The gummas of late secondary and tertiary syphilis reveal necrotizing granulomas with multinucleated Langerhans-type giant cells and obliterative endarteritis. Spirochetes are sparse and only rarely observed in gummas. Recurrent laryngeal nerve paralysis may be seen in neurosyphilis as a manifestation of central nervous system disease, along with other cranial nerve deficits or as an isolated nerve palsy. Concomitant HIV infection is believed to increase the incidence of tertiary syphilis and neurosyphilis.

Special Studies

The classic dark-field examination is made by examining transudate from a chancre suspended in saline for the motile spirochetes. A more specific form of this examination is the dark-field direct immunofluorescent antibody test for T. pallidum , which can be performed on dried fixed tissue smears. Immunohistochemical staining, with commercially available polyclonal antibody, may be helpful in cases that clinically and histologically suggest primary or secondary syphilis, but are negative by silver staining.

Differential Diagnosis

Lymphoplasmacytic infiltrates may also be seen in nonspecific laryngitis and in the early stages of scleroma (see later). Blastomyces infection is classically known for inducing a hyperplastic hyperkeratotic mucosal reaction, similar to condyloma latum. Clinical history and special stains and/or cultures should distinguish blastomycosis from condyloma latum. The hyperplasia of condyloma latum may also be confused with laryngeal malignancy. Careful histologic sampling will usually allow separation of these two entities. The differential diagnosis of the granulomatous inflammation of tertiary syphilis includes mycobacterial and fungal infections. These latter infections can be separated on the basis of culture and special stains. Laryngeal inflammatory pseudotumor (inflammatory myofibroblastic tumor) may also be characterized by a dense lymphoplasmacytic infiltrate, but it will have a more prominent reactive myofibroblastic component.

Treatment

Penicillin G is the drug of choice for syphilis. Patients allergic to penicillin may be treated with erythromycin, tetracycline, or ceftriaxone.

Clinical Features

The term scleroma is preferred over rhinoscleroma because the entire upper aerodigestive tract may be involved, from nose to trachea, as well as the nasopharynx, paranasal sinuses, and Eustachian tube. In a recent series of 134 cases from the Highlands region of New Guinea, 53% were confined to the nose and nasopharynx, 6.7% to the nose and eustachian tube, with 3% involving the middle ear, and 12.7% extending to the larynx and trachea. Primary laryngeal involvement without involvement of the nose was seen in 8.2% of patients. Usually, scleroma initially presents in the second to fourth decades of life, with a female predominance. The nasal cavity and sinuses are most frequently involved. In the larynx, the most common site of involvement is the subglottic region. The natural disease course evolves through three stages. The early stage is the atrophic catarrhal stage in which the mucosa is reddened and atrophic, with foul purulent discharge and crusting. The clinical differential diagnosis in this early stage includes infection with Klebsiella ozaenae . The second stage or granulomatous stage occurs months to years later, with waxy, ulcerating inflammatory masses that distend and deform the mucosal surfaces. The inflammatory masses extend through the external nares in severe cases and may distort the soft tissues of the midface, resulting in a rhinoceros-like appearance. The clinical differential diagnosis includes leprosy and syphilis. The final sclerotic stage is characterized by fibrosis and inflammation and culminates in stenosis.

Common symptoms of laryngeal involvement include progressive dyspnea, cough and hoarseness. Involvement of the subglottis may culminate in subglottic stenosis.

Pathologic Features

Histologically, the catarrhal stage is dominated by nonspecific lymphoplasmacytic infiltrate; bacilli-laden foamy macrophages (Mikulicz cells) are sparse. Mikulicz cells are most abundant in the nodular granulomatous stage. True granulomas with epithelioid histiocytes are not seen. Plasma cells and Russell bodies are prominent in early infection. The final sclerotic stage reveals dense fibroconnective tissue with a relative paucity of inflammatory cells ( Fig. 5.7 ).

Special Studies

K. rhinoscleromatis (Frisch bacillus) is a gram-negative bacillus. Special stains, such as periodic acid–Schiff (PAS), with and without diastase, Hotchkiss-McManus, and Warthin-Starry silver stains will reveal bacterial rods within these histiocytes; the Warthin-Starry silver stain is most sensitive. Immunohistochemistry on formalin-fixed, paraffin-embedded tissues against type III Klebsiella antigen is also sensitive and specific. Routine cultures for K. rhinoscleromatis (on MacConkey medium) may be positive only in 50% of cases and are more likely to be positive in the nodular stage.

Differential Diagnosis

The differential diagnoses include atypical mycobacterial infection, which also appears as a histiocytic infiltrate rather than a granulomatous reaction. A Ziehl-Neelsen stain can rule this out. Lepromatous leprosy also appears as a diffuse histiocytic infiltrate (Virchow cells) and should be ruled out by a Fite-Faraco stain. When a lymphoplasmacytic infiltrate dominates the histology, the diagnosis of syphilis should also be considered.

Treatment and Prognosis

Long-term (3–6 months) parenteral antibiotic therapy, such as with tetracycline, streptomycin, chloramphenicol, or ciprofloxacin (1 g/day) has been reported. Surgery for early acute disease may increase disease dissemination and should be reserved for more advanced disease. Reconstruction may be indicated in the sclerotic stage. Fatal sclerotic airway obstruction may occur. In a recently published series, 74.9% of patients were treated medically and 26.1% required surgery and 61.9% of medically treated patients were cured, while only 19.4% of surgically treated patients had good outcomes. Long-term clinical and endoscopic follow-up is necessary until obtained biopsies are negative. Three patients with a familial history of scleroma developed early onset disease. Squamous carcinoma has purportedly been associated with scleroma, but adequate documentation is lacking.

Pathologic Features

The pale yellow sulfur granules or grains (originally called drusen ) observed clinically are microcolonies of bacilli. Microscopically, Actinomyces typically cause suppurative inflammation with colonies of filamentous bacteria, which appear as round or oval basophilic masses with a radiating arrangement of eosinophilic terminal “clubs,” measuring 1 to 2 mm in diameter. They often contain calcium phosphate. These colonies of bacteria are usually surrounded by neutrophils, foamy macrophages, and occasionally giant cells (see Fig. 5.8B ). Special stains are helpful to confirm the diagnosis, as Actinomyces stains with silver impregnation techniques, and Brown and Brenn staining (gram positive).

Differential Diagnosis

The main differential diagnosis is Nocardia. Actinomyces are not acid fast and do not stain with Ziehl-Neelsen stain, although occasionally they may be weakly acid fast. Nocardia are filamentous bacteria that do not stain well with hematoxylin and eosin but do stain well with a modified Ziehl-Neelsen stain. The distinction between these two filamentous bacteria is important, as their sensitivities to antibiotics differ: penicillin is the drug of choice for Actinomyces , whereas Nocardia are unresponsive to penicillin and can be treated with sulfa drugs.

For microbiologic diagnosis of actinomycosis, anaerobic culture is required. It has been claimed that culture results in proper diagnosis in only 20% to 40% of cases, whereas the remaining cases are diagnosed by biopsy. Biopsy is considered as the quickest and most sensitive way of diagnosis actinomycosis.

Treatment

Actinomycosis is usually treated with prolonged high doses of antibiotics, usually penicillin G. Allergic patients may be treated with tetracycline, clindamycin, or erythromycin. Surgery is sometimes needed and is beneficial in cases with extensive necrosis, fistula, and/or a sinus tract, and in patients who do not response to treatment with antibiotics.

Pathologic Features

The pseudohyphae of Candida are thin, regular, and pinched at the point of pseudoseptation, without true branching ( Fig. 5.9 ). Small, oval, globose yeast cells result in a “spaghetti and meatballs” appearance. The inflammatory infiltrate may be acute and nonspecific or granulomatous.

Differential Diagnosis

The differential diagnosis includes other thin, hyphae-forming fungi, but the hypopharynx and larynx are not usually involved with infections by hyphal-forming fungi, such as Aspergillus .

Treatment

Parenteral antibiotic therapy would include fluconazole or ketoconazole. If disseminated disease is present, then systemic antifungal therapy (amphotericin B or flucytosine) is indicated.

Pathologic Features

Biopsy samples taken from laryngoscopy show both spores and broad septate hyphae, the majority of which exhibit acute angle branching on histopathological examination. The hyphae of aspergillus are basophilic with hematoxylin and eosin stain; using silver impregnation method and PAS-D, the circular and uniform calibre of mycelium, with septate hyphae and occasional folds with dichotomous branching are better recognized. Histopathologically, aspergillosis can show necrotizing, suppurative, granulomatous, or pseudomembranous inflammation.

Differential Diagnosis

The main differential diagnosis is with other fungal infections. The presence of septate hyphae with dichotomous branching is diagnostic for aspergillosis.

Treatment

Management of aspergillosis infection remains problematic. In some cases, the removal of the vocal cord lesions during biopsy provides relief of symptoms. Early diagnosis is crucial to prevent further dissemination from superficial to the deep form of the disease, where aspergillus can have hematogenous spread. Antifungal agents may be helpful in treating patients with a normal immune system, but their value in treating immunocompromised patients is more complex.

Clinical Features

Coccidioidomycosis is primarily a self-limiting pulmonary/mediastinal disease transmitted through the inhalation of arthrospores. Approximately 0.5% to 1% of infected individuals develop disseminated disease affecting skin, subcutis, bone, joints, and meninges. Disseminated coccidioidomycosis is more likely to develop in immunosuppressed, rather than immunocompetent, individuals. Laryngotracheal coccidioidomycosis is rare and may be seen with or without concurrent pulmonary disease. Many patients with laryngeal coccidioidomycosis also have dermal, particularly facial, involvement. Patients with upper airway involvement present with hoarseness, stridor, and vocal cord paralysis. Endoscopically, they have erythematous polypoid mucosa that may reach obstructive, life-threatening proportions. Sites of laryngeal involvement include the epiglottis, vestibule, aryepiglottic fold, true vocal cords, anterior commissure, and subglottis.

Pathologic Features

Coccidioides evoke a granulomatous foreign body–type reaction, with a dense chronic inflammatory infiltrate. The fungal spherules are large (30–80 μm), and the capsule is thick with internal and external limits, giving it a double-walled appearance ( Fig. 5.10 ). The endospores are small (2–5 μm) and numerous. The overlying squamous mucosa may be hyperplastic and hyperkeratotic. Serum acute antibodies and a newly converted skin reaction to coccidioidin antigen may be helpful clinical diagnostic adjuncts; these tests may be falsely negative early in the course of infection.

Differential Diagnosis

The differential diagnosis of the spherules includes Rhinosporidiosis seeberi , which are much larger (350 μm) than Coccidioides. R. seeberi also has a thicker, distinctly bilaminated capsule that stains with mucicarmine; the Coccidioides capsule does not. Free endospores may be confused with other yeast or yeast-like structures in their size range that include Blastomyces, Cryptococcus, Paracoccidioides, Sporothrix, Pneumocystis , and Torulopsis . Morphologic features should allow proper classification.

Treatment

Transient acute pulmonary infection usually goes untreated. If the patient has laryngeal infection, as part of a cavitating pulmonary process, surgical debridement may be necessary in addition to antifungal therapy (e.g., ketoconazole, amphotericin B, fluconazole, itraconazole).

Clinical Features

A broad range of manifestations may be seen, from subclinical to clinical infections, in both immunocompetent and immunosuppressed populations. It can manifest with mucocutaneous and/or visceral infection. In many cases, the initial clinical manifestations are intraoral. Lesions are painful and reddened, granular, mulberry-like (framboesiform), or ulcerative. Aspiration leads to pulmonary infection. Laryngeal infection, secondary to pulmonary involvement, is possible and should be considered in the differential diagnosis of laryngeal infections in South American patients. Involvement of the epiglottis and larynx may cause hoarseness and dyspnea. Deforming scarring may result in tracheostomy dependence.

Pathologic Features

Paracoccidioidomycosis causes an ulcerative, densely inflamed granulomatous response. Multinucleated giant cells containing ingested yeast fragments can be seen. The yeast are round and 1 to 30 μm in diameter. The characteristic feature is multiple budding daughter yeasts (2–10 in cells as large as 30 μm) that may virtually rim the mother yeast capsule, giving the appearance of spokes on a mariner’s wheel. This is best observed on Gomori methenamine silver and PAS stains ( Fig. 5.11 ). Paracoccidioides may be birefringent and polarize with a Maltese-cross appearance, although this finding may be seen with other yeast forms. Cultures can sometimes be diagnostic, but Paracoccidioides grows extremely slowly. Polymerase chain reaction can be used as a diagnostic tool to detect Paracoccidioides brasiliensis .

Differential Diagnosis

The small, newly released daughter spores may be confused with other smaller yeasts (e.g., Histoplasma ). A single budding yeast also may resemble Blastomyces , which is the main differential diagnosis (hence the synonym South American Blastomyces ). The diagnosis can be secured by observing the multiple spoke-wheel budding on Gomori methenamine silver stain. The budding of Blastomyces is invariably singular and has a wider neck than that of Paracoccidioides. Blastomyces also has retraction artifact between the yeast form and the capsule. In contrast to the other mycoses, there are no reports of mycelia in tissues with paracoccidiomycosis.

Treatment

Antifungal therapy is indicated (e.g., ketoconazole, amphotericin B, itraconazole).

Clinical Features

Blastomyces may cause disease either through inhalation or traumatic inoculation into skin. It may present with acute onset of fever, productive cough, and myalgias, or with an insidious onset of weight loss, malaise, anorexia, and a chronic cough, mimicking tuberculosis. Patients experiencing direct inoculation into soft tissues or the upper airway present with local symptoms, such as an ulcerating mass, but no systemic symptoms. An immunosuppressive condition precedes the fungal disease in 25% of patients. Diabetes mellitus is also commonly associated with blastomycosis.

The larynx appears to be a target for the organism. In a recent report of 102 patients with blastomycosis seen at the Mayo Clinic, five patients had laryngeal lesions. Laryngeal blastomycosis appears as an erythematous or white mass, with irregular borders that may immobilize the vocal cords, an appearance that mimics carcinoma. Deep laryngeal fissures or laryngocutaneous fistulas may form. Quite a few laryngeal carcinomas have been reported, after which a rereview of the biopsy or laryngectomy specimens revealed not cancer but blastomycosis.

Pathologic Features

Blastomyces has the distinct ability to induce a hyperplastic, hyperkeratotic verrucoid response, mimicking squamous carcinoma or verrucous carcinoma. Acute and chronic granulomatous reactions with microabscesses and necrosis are seen. The organism is round, 6 to 15 μm wide, with very distinctive thick, doubly refractile walls, and characteristic broad-based single buds. The daughter buds are frequently as large as the mother cell before detachment. Another characteristic feature of Blastomyces is the retraction artifact between the cell wall and the protoplasm, seen on hematoxylin and eosin stain ( Fig. 5.12 ). It is relatively easy to identify the fungus in tissue exudates and not particularly difficult to culture with a 2- to 4-week incubation period. Serology and skin testing are not useful. Commercial test kits are available that facilitate early identification of mycelial cultures by recognition of fungus-specific exoantigens or unique ribonucleic acid (RNA) sequences.

Differential Diagnosis

The differential diagnosis includes Paracoccidioides (see Fig. 5.11 ), Cryptococcus , and Sporothrix schenkii . The broad budding dumbbell- or lollipop-shaped appearance of Blastomyces aids in distinguishing it from the similarly sized Cryptococcus and S. schenkii . However, Blastomyces budding is not always observed. Both Blastomyces and Cryptococcus have cell walls that stain strongly with PAS and Gomori methenamine silver. The cell wall of Blastomyces will stain weakly or not at all with the mucicarmine stain, whereas Cryptococcus will react strongly with the mucicarmine stain. Although Blastomyces can cause infections in the immunocompromised, other fungal infections (e.g., histoplasmosis, cryptococcosis) are more likely to occur.

Treatment

Antifungal therapy is indicated (ketoconazole, amphotericin B, or itraconazole), and surgical reconstruction may be necessary.

Clinical Features

Cryptococcal laryngitis has been seen in patients with acquired immunodeficiency syndrome (AIDS), either with previous or concurrent pneumonia, or as isolated laryngeal lesions. It may also occur in immunocompetent hosts, with or without concomitant pulmonary disease, as well as in association with exposure to inhaled corticosteroids. Clinically, cryptococcal laryngitis typically has an exudative or a wart-like appearance caused by the epithelial hyperplasia, which may mimic carcinoma, but it may rarely present as a smooth-surfaced mass.

Pathologic Features

Cryptococcal infection may be associated with a granulomatous reaction. Induced epithelial hyperplasia can be seen. The organisms are extracellular. The yeast capsule does not stain with hematoxylin and eosin, although it may accentuate their nuclei. Gomori methenamine silver will stain the organism, whereas mucicarmine and digested PAS stain will accentuate the polysaccharide capsule ( Fig. 5.13 ). Uncollapsed round yeast capsules are the size of erythrocytes (6–7 μm) but may be as large as 20 μm. Collapsed deformed yeast takes on a boat-like or sickle shape, similar to Pneumocystis . Single budding yeast with narrow necks may be seen. Capsule-deficient Cryptococcus , seen in AIDS, may confound the diagnosis.

Differential Diagnosis

The differential diagnosis includes yeast forms, such as S. schenkii, Pneumocystis carinii, Torulopsis glabrata, B. dermatitidis , and Histoplasma capsulatum. B. dermatitidis and Cryptococcus are the only two yeast forms with a polysaccharide cell wall that stain with digested PAS. Blastomyces can be distinguished from Cryptococcus by its wider budding isthmus, protoplasmic retraction artifact, and lack of strong reaction with the mucicarmine stain. The other organisms can be distinguished from Cryptococcus based on their size and shape. H. capsulatum is smaller and intracellular; S. schenkii has football-shaped yeasts, in addition to the rounded forms; P. carinii is approximately the same size as Cryptococcus but lacks the variation in size, the mucinophilic capsule, and the budding forms of Cryptococcus.

Treatment

Amphotericin B, possibly in conjunction with flucytosine, is indicated for extrapulmonary cryptococcal infection; however, localized disease may be amenable to laser excision.

Clinical Features

The most common manifestation of histoplasmosis is a subclinical pulmonary infection, usually because of a small exposure source and normal patient immunity. Massive inhalation can lead to acute pneumonia. Serious sequelae include chronic cavitating, fibrosing pulmonary infection, sclerosing mediastinitis, and disseminated infection with bone marrow and adrenal involvement. Symptomatic disseminated histoplasmosis occurs mostly in immunodeficient patients or those at the extremes of age. Disseminated disease is thought to be caused by reinfection or less frequently reactivation of latent disease. Upper aerodigestive tract features of disseminated histoplasmosis include cervical adenopathy, pharyngitis, tonsillitis, and ulcerating oral lesions.

Occasionally, oropharyngeal histoplasmosis may be the primary disease presentation, causing painful, indurated, ulcerating, or verrucoid lesions that may erode bone. Plaques, nodules, ulcers, and indurated masses may be seen in the oral cavity and larynx, and exophytic lesions may clinically mimic carcinoma. Ulcerating facial lesions may also occur around the nose and mouth. Laryngeal histoplasmosis can be part of a primary upper aerodigestive tract presentation or in association with active pulmonary histoplasmosis. The diagnosis is made by biopsy, examination of direct smears, and cultures.

Pathologic Features

Histoplasma microorganisms are 2- to 4-μm oval to spherical “intracellular and extracellular petite hematoxylinophilic bodies, each surrounded by a small halo.” The halo is caused by cytoplasmic retraction from the capsule. Careful observation will reveal intracellular nuclei. A granulomatous reaction may be present. Purulent inflammation may be seen in immunosuppressed patients. The overlying mucosa can be hyperplastic. Hematoxylin and eosin staining is optimal for observing these organisms because it emphasizes the intracellular site and the halo effect around each organism, allowing observation of the nuclei ( Fig. 5.14 ). The organism does stain with Gomori methenamine silver, but the high background may make this stain unsuitable for evaluation. PAS will stain the organisms and their capsule with less background. Solitary and multiple thin-necked budding may be seen. A touch preparation from a mucosal lesion is superior in revealing the fine morphology of Histoplasma and, if possible, should be an adjunct to tissue biopsy. H. capsulatum requires as long as 6 weeks to grow in culture.

Differential Diagnosis

The histologic differential diagnosis includes other small intracellular organisms, such as Leishmania tropica and L. mexicana complex, Trypanosoma cruzi , poorly encapsulated Cryptococcus , and small tissue forms of B. dermatitidis , which may also cause mucocutaneous lesions. Laryngeal leishmaniasis (originally diagnosed as histoplasmosis) has been reported as a sequelae of a cutaneous infection (Oriental sore).

Leishmania and Trypanosoma are within the same size range as Histoplasma but lack the prominent clear halo of the latter. Leishmania and Trypanosoma can be seen with hematoxylin and eosin and reticulin stains. Histoplasma is a round to oval organism; Leishmania and T. cruzi have a “diaper pin” shape. Histoplasma will stain with Gomori methenamine silver and PAS stains, but Trypanosoma and Leishmania will not. Both Trypanosoma and Leishmania have intracellular kinetoplasts that are not visualized on hematoxylin and eosin–stained sections, but may be seen on Giemsa-stained touch preparations. Poorly encapsulated Cryptococcus usually retains some mucinophilia and so may be distinguished from Histoplasma. B. dermatitidis may be distinguished from Histoplasma by its broad-based pattern of budding.

Treatment

The distinction between Histoplasma and Leishmania is particularly important in cases of disseminated infection because the treatments are very different (antifungal agents vs. antiprotozoal agents). Histoplasmosis can be treated with itraconazole, ketoconazole, or amphotericin B. Laryngeal histoplasmosis requires a prolonged course of therapy; it is generally many months before the hoarseness completely resolves. Prophylaxis with itraconazole (200 mg/day) in patients with HIV and CD4 counts less than 150 cells/mm ³ is highly effective and should be considered if the case rate of histoplasmosis exceeds 10 cases per 100 patient-years.

Clinical Features

Rhinosporidium most commonly infects the nasal cavity, causing friable, lobulated red or pink polyps that may become massive and extend posteriorly to fill and obstruct the nasopharynx, oropharynx, and hypopharynx. Extranasal manifestations are relatively uncommon. Conjunctival infection may also occur, usually after local injury. Laryngeal involvement by Rhinosporidium is extremely rare and always secondary to nasopharyngeal involvement.

The nature of the etiologic agent of rhinosporidiosis has long been elusive. Originally, it was considered a fungus and more recently has been classified as a blue-green algae. However, recent molecular biological investigations have led to the classification of Rhinosporidium as a Mesomycetozoea , a novel clade that is phylogenetically at the animal-fungus divergence in the evolutionary tree.

Pathologic Features

In hematoxylin-eosin–stained tissue, an intense acute and lymphoplasmacytic infiltrate is present. Cysts (also referred to as spherules or sporangia ) are numerous, round, large (100–350 μm), and thick walled ( Fig. 5.15 ). The thick cyst wall stains with hematoxylin and eosin, Gomori methenamine silver, digested PAS, and mucicarmine; it is also birefringent. The largest, most mature cysts are closest to the mucosal surface. Hundreds to thousands of small (2- to 9- μm) spores are seen within mature cysts. The spores are initially uninuclear and range in size from 10 to 100 μm in diameter, but on maturation are multinucleated, forming clusters of 12 to 16 “naked” nuclei. Mitotic figures within these spores are infrequently observed. On maturation, the cysts extrude the spore morulas into the surrounding tissue from a pore. In cases of disseminated rhinosporidiosis, it is possible to find single spores in body fluids, such as urine.

Differential Diagnosis

The differential diagnosis of Rhinosporidium is mainly with mucosal Coccidioides immitis . In fact, Seeber initially believed that Rhinosporidium was related to C. immitis ; but its spherules are not as large (60 μm); its walls are not as thick, birefringent, or mucinophilic; and its endospores are not as numerous. If one sees only the extruded mature spores, which range from 2 to 9 μm in diameter, one might consider all other yeast forms within that range.

Oncocytic schneiderian papilloma (cylindrical cell papilloma) may also be confused histologically with rhinosporidiosis; however, the cysts of the former are intramucosal and contain mucin and polymorphonuclear cells versus the spore-filled submucosal cysts of the latter.

Treatment

Surgical debridement is indicated for these polypoid lesions. Response to dapsone therapy has been demonstrated.

Clinical Features

The larynx and trachea may be sites for ulcerative CMV infections, even in the absence of CMV pneumonitis. The clinical differential diagnosis of ulcerative laryngeal lesions in HIV patients would also include candidal and herpetic infection and may be resolved by tissue biopsy, touch preparation, or smear plus cultures.

Vocal cord paralyses (without mucosal ulceration) are seen because of laryngeal neuritis: CMV inclusions have been demonstrated at autopsy within the recurrent laryngeal nerve. This mechanism may explain the case of pharyngeal CMV infection causing vocal cord immobility. Concomitant supraglottic diffuse large cell lymphoma and CMV epiglottitis have been reported.

Pathologic Features

CMV inclusions are most frequently seen in the endothelial cells adjacent to areas of ulceration. The classic CMV-infected cell has a large pink intranuclear inclusion, surrounded by a clear halo and, less commonly, amphophilic smaller cytoplasmic inclusions ( Fig. 5.16 C and D ). The combination of intranuclear and intracytoplasmic inclu sions is seen only after the viral infection undergoes a replication phase, which occurs in a minority of infected cells.

Special Studies

Before replication, infected cells produce great quantities of immediate early antigen and early antigen, which may be detected immunohistochemically as intranuclear inclusions. This accentuates the importance of special studies in the absence of classic CMV inclusions. This also explains the enhanced sensitivity to immunohistochemistry for early antigen compared with in situ hybridization for the CMV genome in early infections lacking classic histology.

Differential Diagnosis

The characteristic appearance of productively infected cytomegalic cells, with their intranuclear and intracytoplasmic inclusions, leaves little room for other possibilities. However, in early infections, enlarged “funny-looking” cells are seen, which may raise the possibility of other infections, such as herpes simplex virus (HSV) infection. Slowly resolving mucocutaneous herpetic ulcers and disseminated infection can occur in AIDS patients and possibly extend to the hypopharynx and larynx. However, primary laryngotracheal HSV infection is an extremely rare occurrence. HSV laryngitis is more likely to be seen in the context of HSV pneumonitis, usually in transplant recipients, burn victims, and the immunocompromised. It can manifest as vesicular or ulcerative lesions or vocal cord paralysis.

HSV-infected cell nuclei become enlarged and reveal peripheral chromatin beading and homogeneous ground-glass inclusions that may be basophilic or “cleared out.” Multinucleated HSV syncytial cells also contain intranuclear inclusions and cytoplasmic inclusions. The nuclei of these multinucleated cells may mold with each other rather than overlap. Immunohistochemistry on formalin-fixed, paraffin-embedded biopsy specimens for HSV-1 and HSV-2 and CMV antigens can be helpful in making the distinction between HSV and CMV infections. Rarely, in immunocompromised patients, one may see both infections in one patient (see Fig. 5.16 ).

Treatment

Ganciclovir or Foscarnet may be used to treat CMV laryngitis.

Clinical Features

Most cases of trichinosis are self-limited; the severity generally depends on inoculum size. The acute stage of trichinosis can start 10 days to 2 weeks after ingestion and last approximately 2 months. Trichinosis initially presents with fever, nausea, vomiting, myalgias, headache, fatigue, and diarrhea. After migration from the host small intestine, the initial site of infestation, Trichinella becomes encysted in skeletal muscle; it especially favors muscles with a rich blood supply, such as the extraocular muscles, intrinsic laryngeal muscles, the diaphragm, and the deltoid and gastrocnemius muscles. After the first week, the symptoms correspond to peripheral migration of the larvae into muscle; they include periorbital or facial edema, myositis, blurry vision, and peripheral eosinophilia. Eye movement and swallowing may be painful, and there is profound diffuse muscle weakness. Parasite invasion into the lungs, heart, and central nervous systems is infrequent, and fatalities are rare.

In late-stage infection, acute symptoms may disappear, but myalgia and fatigue can persist. The parasite alters the myocyte intracellular environment so that both can remain viable for years. Accordingly, Trichinella may be an incidental finding, many years after infection, in the sternocleidomastoid muscle of radical neck dissections or within the intrinsic laryngeal muscles in laryngectomy specimens ( Fig. 5.17 ).

Pathologic Features

Trichinella (genus Trichina , Greek, “hair”) was first histologically identified at autopsy by James Paget as a medical student. The larvae appear as a tightly coiled worm within an intramuscular double-walled capsule. If the larvae are missed on muscle biopsy because of sampling error, nonspecific myositis may be seen. Calcified cysts denote remote infection.

Treatment

If Trichinella is an incidental finding in a laryngectomy specimen, no treatment is indicated. Treatment consists of steroids and anthelminthics (e.g., mebendazole, albendazole), which must be administered before the end of the acute phase for relief of the acute migratory symptoms.

Pathologic Features

The ova of Schistosoma may be calcified and are usually in a granulomatous reaction or in receding inflammation. S. mansoni and S. haematobium ova are elongated and oval. S. mansoni has a prominent, pointed lateral spine, and S. haematobium has a prominent terminal spine. S. japonicum ova are rounder and plumper than S. mansoni and S. haematobium ova, with a small lateral spine.

Clinical Features

Cutaneous leishmaniasis is marked by skin papules that progress and ulcerate. Satellite nodules and regional lymphadenopathy are seen. Cutaneous leishmaniasis may progress to mucocutaneous disease. Mucocutaneous leishmaniasis is characterized by multiple mucosal ulcerations that develop after hematogenous spread; buccal mucosa, lips, palate, tongue, tonsils, and the larynx can be affected. These mucosal ulcerations can clinically mimic neoplasia. Visceral leishmaniasis (kala azar: Hindi, black fever) may have an incubation period from weeks to months affecting the liver, spleen, bone marrow, lymph nodes, heart, and kidneys, causing weight loss, hepatosplenomegaly, anemia, and thrombocytopenia. Immunosuppression associated with infection with human immunodeficiency virus and systemic autoimmune diseases is known to increase the incidence of visceral leishmaniasis in nonendemic areas. Laryngeal leishmaniasis has also been reported in association with inhaled corticosteroids. Laryngeal leishmaniasis can occur as part of mucocutaneous leishmaniasis, or visceral leishmaniasis, as an isolated disease, or in human immunodeficiency virus–associated visceral leishmaniasis.

Pathologic Features

Isolated ulcerating lesions may develop in the oropharyngeal nasal and laryngeal mucosa, as well as in the anogenital mucosa. Mucocutaneous leishmaniasis is characterized by surface ulceration, granulomatous reaction, dense lymphoplasmacytic infiltrate with necrosis, and granulation tissue. The leishmanial amastigotes are seen in histiocytes, under oil immersion or in hematoxylin-eosin– or Giemsa-stained sections. The number of amastigotes varies with host immunity status: tissue from patients with isolated lesions and adequate immunity will reveal epithelioid histiocytes and sparse organisms, whereas those from anergic patients with diffuse involvement will reveal foamy macrophages with abundant amastigotes. The diagnosis can be confirmed by culture, enzymatic analysis of the isolates and polymerase chain reaction (PCR). Treatment consists of antimonial compounds, usually meglumine antimonate.