2.1

Larynx

Laryngeal blastomycosis is the most commonly reported presentation of B . dermatitidis involving the head and neck structures with 28 cases documented in the literature . Patients almost universally presented with progressive hoarseness of one to several months duration. Presence of cough, sputum production, dysphagia, or dyspnea was variable; hemoptysis was occasionally reported. While pulmonary involvement varied among these patients, its presence appeared to be associated with poorer outcomes. Examination by direct laryngoscopy revealed grossly polypoid masses described as exophytic or verrucous, located on false or true vocal cords. Hypomobility of one or both cords was common. When mentioned, laboratory evaluation without any gross abnormality was typical.

The presence of an infiltrative polypoid mass of the laryngeal structures was reliably identified in most cases by direct laryngoscopy and radiography. The initial working differential diagnosis of a grossly polypoid mass of the larynx was carcinoma, tuberculosis, and, less commonly, polyposis.

Biopsy was performed in all cases, universally demonstrating epithelial cell atypia and pseudoepitheliomatous hyperplasia. The presence of hyperplasia combined with the absence of identifiable yeasts on H&E staining often prompted a diagnosis of laryngeal or glottic carcinoma. However, broad-based budding yeasts were successfully identified in all instances in which GMS stain was eventually applied to the biopsy samples.

Consideration of blastomycosis frequently occurred only after initial therapies for other suspected etiologies failed. Misdiagnosis of malignancy led to radiation therapy or total laryngectomy in several cases . Where surgical resection was performed, lesions rapidly recurred . In one case sarcoidosis was suspected until the patient’s condition deteriorated on oral steroids . In another, diagnosis was made only after progressive disease dissemination and the patient expired about a year from the onset of symptoms .

Administration of IV Amphotericin B (AmB) produced complete resolution of symptoms within one to two months in most patients. Patients with longer duration of symptoms prior to treatment were more likely to develop long-term sequelae, most commonly persistent hoarseness. Chronic inflammation and persistent fibrosis resulting from particularly long delays in treatment were reported to cause irreversible laryngeal stenosis necessitating permanent tracheostomy . Also seen in prolonged disease courses were esophageal stricture, extension into perilaryngeal structures and overlying skin, or even chronic inflammation of the larynx producing secondary dysplastic changes.

2.2

Oral cavity/tongue

Seven case reports and two case series’ discuss blastomycotic infection of the oral cavity or tongue in 16 patients . Of the patients described, only two endorsed the typical initial symptoms of blastomycosis such as cough, chest discomfort, or weight loss and only five had documented radiographic evidence of pulmonary blastomycosis . Most commonly, patients presented with intraoral pain and tenderness as well as a progressively enlarging growth in the area of discomfort. Some cases began as an initial lesion at a different site with the subsequent development of a mass in the mouth.

Patients commonly presented with a papular or verruciform lesion of the tongue or oral mucosa that was usually several centimeters in size. Gradual enlargement over a period of months was often reported and lesions occasionally ulcerated. In several instances the gross findings raised an initial concern for a neoplastic process . In one case the clinical picture of a ruptured mandibular mass draining foul-smelling pus led to an initial suspicion for Actinomyces as the responsible pathogen . A common associated finding with these intraoral lesions was simultaneous or subsequent spread of infection to the mandible, with at least five cases documenting bone involvement . One patient experienced extensive skull defects in the left temporal region as well . Hard, swollen submandibular glands and lymph nodes have been appreciated on exam .

Confirmation of blastomycosis in these cases was most often achieved via histologic findings, and in some cases culture, after biopsy of the lesion. Childrey and colleagues reported using surgical diathermy on an isolated tongue lesion without recurrence . Other reports of surgical intervention were in conjunction with radiation and/or antifungal therapies . Most patients improved on antifungal therapy alone. Resolution typically occurred in a period of weeks to months without recurrence.

2.3

Neck

Nine cases of blastomycosis involving the noncutaneous tissues of the neck have been reported . Five patients presented with typical symptoms of pulmonary blastomycosis and seven showed radiographic evidence of pulmonary involvement. The thyroid gland was involved in five cases, with either parenchymal invasion or abutment of the capsule. In one case, the infection in the neck appeared to be a direct extension of a pulmonary lesion through the thoracic outlet .

The typical clinical presentation for blastomycosis of the neck is a firm, fixed mass in the anterior or lateral neck with overlying erythema in association with symptoms of pulmonary infection. The majority of neck lesions were very tender. Their sizes and rates of growth were variable; some developed rapidly over a period of days, while others progressed slowly over the course of a year or more. One patient reported a stable neck mass for one year followed by a period of accelerated growth over three months . The location of these masses may lead to characteristic symptoms due to mass effect, such as dysphagia, or shoulder pain and atrophy of the latissimus dorsi secondary to compression of the cervical nerve roots . Tender cervical, facial, and submandibular lymphadenopathy was also observed .

Confirmation of B . dermatitidis infection in the neck was most often made by culture and staining of fluid obtained by fine-needle aspiration (FNA) performed as part of the usual workup for a neck mass. Ultrasound provided the best initial description of size and morphology of the mass. Magnetic resonance imaging (MRI) and computerized tomography (CT) were useful in evaluating the neck lesion and primary pulmonary process, and in searching for any additional unsuspected foci of infection.

Response to treatment of neck infections does not appear to differ from that of other forms of blastomycosis. Complete resolution of symptoms occurred in all patients in this series within a period ranging from a few months to more than a year after appropriate antifungal therapy.

2.4

Ear and mastoid

B . dermatitidis as a cause of otitis and otomastoiditis is described in only six published reports comprising seven patients . Five patients had extra-otic manifestations that implicated entry by lymphohematogenous dissemination or by extension from infected contiguous structures. Istorico et al. described an adult patient who presented with otitis media along with osteomyelitis of the ankle, dermatitis, and diffuse infiltrates on chest x-ray, despite an absence of respiratory complaints . The authors also presented a 12-year-old child with otitis media, a peripharyngeal mass, and infiltrates on chest radiography. Five of the seven patients had no radiographic or clinical evidence of pulmonary involvement.

Most patients presented with several months of ear pain, feeling of fullness, drainage, and/or hearing loss, often after failing courses of conventional antibiotic therapies for acute otitis media. Otoscopic exam showed purulent exudate and polypoid friable granulation tissue often adherent to the auditory canal. The tympanic membrane occasionally demonstrated granulation but was generally indistinguishable from acute bacterial otitis media. In several cases, the gross appearance of lesions and treatment resistance led clinicians to consider a neoplastic process.

Imaging studies can be helpful in determining the focus of disease and involvement of contiguous structures, though some patients may have initial negative findings . Radiographically defining the extent of disease is especially important since involvement of osteoarticular structures can lead to persistent symptomatology. Louis and Lockey described an adult patient in whom the final diagnosis of blastomycotic osteomyelitis of the middle ear cleft was made five years after her initial presentation with recurrent serous otitis media and progressive hearing loss . Unfortunately, this patient underwent multiple unsuccessful surgical interventions during this protracted period of uncertain diagnosis. Similarly, Farr et al. observed temporal bone osteomyelitis caused by B . dermatitidis that presented as chronic serous otitis media refractory to conventional medical and surgical management .

Oral antifungal therapy appears to be effective even when contiguous structures are involved, with reports of symptom resolution and improvement of hearing loss after several months of treatment. However, the duration and extent of infection may cause scarring and permanent structural changes of affected organs. Blackledge and Newlands reported persistent middle ear abnormalities even after antifungal therapy and resolution of temporal bone blastomycotic osteomyelitis .

2.5

Nose and paranasal sinuses

Six cases of blastomycosis infecting the nose and paranasal sinuses have been reported . The clinical characteristics of blastomycosis in these cases varied greatly. Often an initial focus of infection was noted clinically which worsened over a period of months. Descriptions of nasal findings included a crusted and papillomatous lesion and a thick granulomatous mass . In at least two cases the lesion was presumed to be neoplastic in nature based upon the initial gross inspection . In one case there was perforation of the nasal septum . Infraorbital or zygomatic swelling was another notable sign, with patients often experiencing pressure sensations or tenderness over these areas . Symptoms secondary to the location of the infection have included proptosis and airway obstruction, as well as edema, erythema, or induration overlying the affected area.

Consistent with the classically described pathophysiology of dissemination from a primary pulmonary focus, five of the six cases demonstrated positive findings on chest x-ray. Of these, three endorsed pulmonary symptoms at initial presentation. Day et al. reported the case of a patient being effectively managed with ketoconazole for pulmonary blastomycosis who subsequently developed blastomycosis of the right maxillary sinus after a period of medication non-compliance . In a separate case, maxillary sinusitis caused by B . dermatitidis began 13 months after a patient was treated for pulmonary blastomycosis .

In almost all cases a definitive diagnosis was made following histologic analysis of tissue biopsy. Often medical management alone was effective , though in other cases surgical interventions served as an adjunct for symptomatic management and debridement of devitalized tissue . Despite resolution of acute infection with antifungal therapy, both multiple recurrences of disease and irreversible bony defects have been reported .

2.6

Skull base, orbit, and calvarium

Blastomycosis infections of the skull base, orbit, and calvarium have been reported . Most commonly these locations are reached by direct extension of granulomatous inflammation from other contiguous sites. Extension into the petrous apex has occurred in patients presenting with ear infection . These patients initially describe otalgia, otorrhea, hearing loss, tinnitus, headache, and facial weakness and are subsequently found to have more extensive invasion of the temporal bone on CT. These infections may be very aggressive causing dehiscence of the carotid canal, as well as infiltration of the mastoid air cells, infratemporal fossa, and pterygopalatine fossa .

In some cases, intracranial spread has also involved the clivus and middle cranial fossa . In one particularly insidious case, the patient presented with progressive bilateral vision loss for seven months and was found to have extensive destructive lesions of the skull base, obliterating the suprasellar region, displacing the pituitary stalk, engulfing the cavernous portions of both carotids, and compressing the brainstem anteriorly . At six-month follow-up, this patient had yet to regain visual acuity.

Presentation with visual symptoms has also occurred due to direct involvement of the orbit. Li et al. described a patient who presented with sharp eye pain and rapidly deteriorating vision . After the diagnosis remained elusive and symptoms progressively worsened over a three-month period, the patient required enucleation of the globe and was found to have extensive intraocular disease and retroorbital abscess, which was confirmed as blastomycosis on biopsy. In another case report, the patient presented with a fluctuant mass over the left temple and exophthalmos . Plain films of the skull revealed lytic and sclerotic destruction of the temporal bone and orbit. After about a year of treatment with AmB, the patient was found to have a persistent orbital abscess, which eventually responded to incision and drainage followed by a second course of treatment with AmB.

Invasion and destruction of other parts of the bony skull have also occurred in several cases. Devgan et al. described a patient who initially presented with swelling in the frontal and supraorbital regions along with upper respiratory symptoms . Radiologic studies identified a cystic lesion in the parietal region, infiltration and demineralization of the frontal bone, and invasion of the maxillary and ethmoid sinuses. Bell and colleagues reported a patient with multiple osteolytic lesions of the bony skull after initial presentation with toothache . Finally, Gil and Gerard reported a large case series which included three children under ten years old who had involvement of the scalp and “skull bones,” though no further information is given regarding their presentation, diagnosis, or treatment course .

In general, treatment of blastomycosis of the skull base and bony calvarium has been successful using standard pharmacologic protocols. However, by nature of their location these lesions tend to be more destructive and leave behind more residual damage relative to other sites in the head and neck. This is especially true of lesions that involve the cranial nerves and sensory organs, resulting in permanent vision and hearing loss . Facial nerve function eventually returned in all cases in which it was reportedly involved .

2.1

Larynx

Laryngeal blastomycosis is the most commonly reported presentation of B . dermatitidis involving the head and neck structures with 28 cases documented in the literature . Patients almost universally presented with progressive hoarseness of one to several months duration. Presence of cough, sputum production, dysphagia, or dyspnea was variable; hemoptysis was occasionally reported. While pulmonary involvement varied among these patients, its presence appeared to be associated with poorer outcomes. Examination by direct laryngoscopy revealed grossly polypoid masses described as exophytic or verrucous, located on false or true vocal cords. Hypomobility of one or both cords was common. When mentioned, laboratory evaluation without any gross abnormality was typical.

The presence of an infiltrative polypoid mass of the laryngeal structures was reliably identified in most cases by direct laryngoscopy and radiography. The initial working differential diagnosis of a grossly polypoid mass of the larynx was carcinoma, tuberculosis, and, less commonly, polyposis.

Biopsy was performed in all cases, universally demonstrating epithelial cell atypia and pseudoepitheliomatous hyperplasia. The presence of hyperplasia combined with the absence of identifiable yeasts on H&E staining often prompted a diagnosis of laryngeal or glottic carcinoma. However, broad-based budding yeasts were successfully identified in all instances in which GMS stain was eventually applied to the biopsy samples.

Consideration of blastomycosis frequently occurred only after initial therapies for other suspected etiologies failed. Misdiagnosis of malignancy led to radiation therapy or total laryngectomy in several cases . Where surgical resection was performed, lesions rapidly recurred . In one case sarcoidosis was suspected until the patient’s condition deteriorated on oral steroids . In another, diagnosis was made only after progressive disease dissemination and the patient expired about a year from the onset of symptoms .

Administration of IV Amphotericin B (AmB) produced complete resolution of symptoms within one to two months in most patients. Patients with longer duration of symptoms prior to treatment were more likely to develop long-term sequelae, most commonly persistent hoarseness. Chronic inflammation and persistent fibrosis resulting from particularly long delays in treatment were reported to cause irreversible laryngeal stenosis necessitating permanent tracheostomy . Also seen in prolonged disease courses were esophageal stricture, extension into perilaryngeal structures and overlying skin, or even chronic inflammation of the larynx producing secondary dysplastic changes.

2.2

Oral cavity/tongue

Seven case reports and two case series’ discuss blastomycotic infection of the oral cavity or tongue in 16 patients . Of the patients described, only two endorsed the typical initial symptoms of blastomycosis such as cough, chest discomfort, or weight loss and only five had documented radiographic evidence of pulmonary blastomycosis . Most commonly, patients presented with intraoral pain and tenderness as well as a progressively enlarging growth in the area of discomfort. Some cases began as an initial lesion at a different site with the subsequent development of a mass in the mouth.

Patients commonly presented with a papular or verruciform lesion of the tongue or oral mucosa that was usually several centimeters in size. Gradual enlargement over a period of months was often reported and lesions occasionally ulcerated. In several instances the gross findings raised an initial concern for a neoplastic process . In one case the clinical picture of a ruptured mandibular mass draining foul-smelling pus led to an initial suspicion for Actinomyces as the responsible pathogen . A common associated finding with these intraoral lesions was simultaneous or subsequent spread of infection to the mandible, with at least five cases documenting bone involvement . One patient experienced extensive skull defects in the left temporal region as well . Hard, swollen submandibular glands and lymph nodes have been appreciated on exam .

Confirmation of blastomycosis in these cases was most often achieved via histologic findings, and in some cases culture, after biopsy of the lesion. Childrey and colleagues reported using surgical diathermy on an isolated tongue lesion without recurrence . Other reports of surgical intervention were in conjunction with radiation and/or antifungal therapies . Most patients improved on antifungal therapy alone. Resolution typically occurred in a period of weeks to months without recurrence.

2.3

Neck

Nine cases of blastomycosis involving the noncutaneous tissues of the neck have been reported . Five patients presented with typical symptoms of pulmonary blastomycosis and seven showed radiographic evidence of pulmonary involvement. The thyroid gland was involved in five cases, with either parenchymal invasion or abutment of the capsule. In one case, the infection in the neck appeared to be a direct extension of a pulmonary lesion through the thoracic outlet .

The typical clinical presentation for blastomycosis of the neck is a firm, fixed mass in the anterior or lateral neck with overlying erythema in association with symptoms of pulmonary infection. The majority of neck lesions were very tender. Their sizes and rates of growth were variable; some developed rapidly over a period of days, while others progressed slowly over the course of a year or more. One patient reported a stable neck mass for one year followed by a period of accelerated growth over three months . The location of these masses may lead to characteristic symptoms due to mass effect, such as dysphagia, or shoulder pain and atrophy of the latissimus dorsi secondary to compression of the cervical nerve roots . Tender cervical, facial, and submandibular lymphadenopathy was also observed .

Confirmation of B . dermatitidis infection in the neck was most often made by culture and staining of fluid obtained by fine-needle aspiration (FNA) performed as part of the usual workup for a neck mass. Ultrasound provided the best initial description of size and morphology of the mass. Magnetic resonance imaging (MRI) and computerized tomography (CT) were useful in evaluating the neck lesion and primary pulmonary process, and in searching for any additional unsuspected foci of infection.

Response to treatment of neck infections does not appear to differ from that of other forms of blastomycosis. Complete resolution of symptoms occurred in all patients in this series within a period ranging from a few months to more than a year after appropriate antifungal therapy.

2.4

Ear and mastoid

B . dermatitidis as a cause of otitis and otomastoiditis is described in only six published reports comprising seven patients . Five patients had extra-otic manifestations that implicated entry by lymphohematogenous dissemination or by extension from infected contiguous structures. Istorico et al. described an adult patient who presented with otitis media along with osteomyelitis of the ankle, dermatitis, and diffuse infiltrates on chest x-ray, despite an absence of respiratory complaints . The authors also presented a 12-year-old child with otitis media, a peripharyngeal mass, and infiltrates on chest radiography. Five of the seven patients had no radiographic or clinical evidence of pulmonary involvement.

Most patients presented with several months of ear pain, feeling of fullness, drainage, and/or hearing loss, often after failing courses of conventional antibiotic therapies for acute otitis media. Otoscopic exam showed purulent exudate and polypoid friable granulation tissue often adherent to the auditory canal. The tympanic membrane occasionally demonstrated granulation but was generally indistinguishable from acute bacterial otitis media. In several cases, the gross appearance of lesions and treatment resistance led clinicians to consider a neoplastic process.

Imaging studies can be helpful in determining the focus of disease and involvement of contiguous structures, though some patients may have initial negative findings . Radiographically defining the extent of disease is especially important since involvement of osteoarticular structures can lead to persistent symptomatology. Louis and Lockey described an adult patient in whom the final diagnosis of blastomycotic osteomyelitis of the middle ear cleft was made five years after her initial presentation with recurrent serous otitis media and progressive hearing loss . Unfortunately, this patient underwent multiple unsuccessful surgical interventions during this protracted period of uncertain diagnosis. Similarly, Farr et al. observed temporal bone osteomyelitis caused by B . dermatitidis that presented as chronic serous otitis media refractory to conventional medical and surgical management .

Oral antifungal therapy appears to be effective even when contiguous structures are involved, with reports of symptom resolution and improvement of hearing loss after several months of treatment. However, the duration and extent of infection may cause scarring and permanent structural changes of affected organs. Blackledge and Newlands reported persistent middle ear abnormalities even after antifungal therapy and resolution of temporal bone blastomycotic osteomyelitis .

2.5

Nose and paranasal sinuses

Six cases of blastomycosis infecting the nose and paranasal sinuses have been reported . The clinical characteristics of blastomycosis in these cases varied greatly. Often an initial focus of infection was noted clinically which worsened over a period of months. Descriptions of nasal findings included a crusted and papillomatous lesion and a thick granulomatous mass . In at least two cases the lesion was presumed to be neoplastic in nature based upon the initial gross inspection . In one case there was perforation of the nasal septum . Infraorbital or zygomatic swelling was another notable sign, with patients often experiencing pressure sensations or tenderness over these areas . Symptoms secondary to the location of the infection have included proptosis and airway obstruction, as well as edema, erythema, or induration overlying the affected area.

Consistent with the classically described pathophysiology of dissemination from a primary pulmonary focus, five of the six cases demonstrated positive findings on chest x-ray. Of these, three endorsed pulmonary symptoms at initial presentation. Day et al. reported the case of a patient being effectively managed with ketoconazole for pulmonary blastomycosis who subsequently developed blastomycosis of the right maxillary sinus after a period of medication non-compliance . In a separate case, maxillary sinusitis caused by B . dermatitidis began 13 months after a patient was treated for pulmonary blastomycosis .

In almost all cases a definitive diagnosis was made following histologic analysis of tissue biopsy. Often medical management alone was effective , though in other cases surgical interventions served as an adjunct for symptomatic management and debridement of devitalized tissue . Despite resolution of acute infection with antifungal therapy, both multiple recurrences of disease and irreversible bony defects have been reported .

2.6

Skull base, orbit, and calvarium

Blastomycosis infections of the skull base, orbit, and calvarium have been reported . Most commonly these locations are reached by direct extension of granulomatous inflammation from other contiguous sites. Extension into the petrous apex has occurred in patients presenting with ear infection . These patients initially describe otalgia, otorrhea, hearing loss, tinnitus, headache, and facial weakness and are subsequently found to have more extensive invasion of the temporal bone on CT. These infections may be very aggressive causing dehiscence of the carotid canal, as well as infiltration of the mastoid air cells, infratemporal fossa, and pterygopalatine fossa .

In some cases, intracranial spread has also involved the clivus and middle cranial fossa . In one particularly insidious case, the patient presented with progressive bilateral vision loss for seven months and was found to have extensive destructive lesions of the skull base, obliterating the suprasellar region, displacing the pituitary stalk, engulfing the cavernous portions of both carotids, and compressing the brainstem anteriorly . At six-month follow-up, this patient had yet to regain visual acuity.

Presentation with visual symptoms has also occurred due to direct involvement of the orbit. Li et al. described a patient who presented with sharp eye pain and rapidly deteriorating vision . After the diagnosis remained elusive and symptoms progressively worsened over a three-month period, the patient required enucleation of the globe and was found to have extensive intraocular disease and retroorbital abscess, which was confirmed as blastomycosis on biopsy. In another case report, the patient presented with a fluctuant mass over the left temple and exophthalmos . Plain films of the skull revealed lytic and sclerotic destruction of the temporal bone and orbit. After about a year of treatment with AmB, the patient was found to have a persistent orbital abscess, which eventually responded to incision and drainage followed by a second course of treatment with AmB.

Invasion and destruction of other parts of the bony skull have also occurred in several cases. Devgan et al. described a patient who initially presented with swelling in the frontal and supraorbital regions along with upper respiratory symptoms . Radiologic studies identified a cystic lesion in the parietal region, infiltration and demineralization of the frontal bone, and invasion of the maxillary and ethmoid sinuses. Bell and colleagues reported a patient with multiple osteolytic lesions of the bony skull after initial presentation with toothache . Finally, Gil and Gerard reported a large case series which included three children under ten years old who had involvement of the scalp and “skull bones,” though no further information is given regarding their presentation, diagnosis, or treatment course .

In general, treatment of blastomycosis of the skull base and bony calvarium has been successful using standard pharmacologic protocols. However, by nature of their location these lesions tend to be more destructive and leave behind more residual damage relative to other sites in the head and neck. This is especially true of lesions that involve the cranial nerves and sensory organs, resulting in permanent vision and hearing loss . Facial nerve function eventually returned in all cases in which it was reportedly involved .