Extrapulmonary intrathoracic blastomycosis : a case report and systematic literature review

The dimorphic fungus Blastomyces dermatitidis, endemic to the Great Lakes region and the Ohio and Mississippi River valley basins in the USA (Chapman et al., 1997, 2008; Proctor & Davis, 1996; Ronald et al., 2009; Winer-Muram et al., 1992), was first recognized in Chicago in 1901 (Ricketts, 1901). In the years since, it has remained endemic, with multiple outbreaks (Kitchen et al., 1977) and an increasing incidence after 1990 (Dworkin et al., 2005; Seitz et al., 2014). Although it primarily affects the lungs, in 20–30 % of cases extrapulmonary sites are involved, including the skin, bones, prostate and central nervous system (Chapman et al., 1997; Kralt et al., 2009; Proctor & Davis, 1996). In 2014, we diagnosed an unusual case of blastomycosis involving the mediastinum in an immunocompetent young woman. In this report, we describe our case and the results of a systematic review on extrapulmonary intrathoracic blastomycosis, focusing on mediastinal involvement.


Introduction
The dimorphic fungus Blastomyces dermatitidis, endemic to the Great Lakes region and the Ohio and Mississippi River valley basins in the USA (Chapman et al., 1997(Chapman et al., , 2008;;Proctor & Davis, 1996;Ronald et al., 2009;Winer-Muram et al., 1992), was first recognized in Chicago in 1901 (Ricketts, 1901).In the years since, it has remained endemic, with multiple outbreaks (Kitchen et al., 1977) and an increasing incidence after 1990 (Dworkin et al., 2005;Seitz et al., 2014).Although it primarily affects the lungs, in 20-30 % of cases extrapulmonary sites are involved, including the skin, bones, prostate and central nervous system (Chapman et al., 1997;Kralt et al., 2009;Proctor & Davis, 1996).In 2014, we diagnosed an unusual case of blastomycosis involving the mediastinum in an immunocompetent young woman.In this report, we describe our case and the results of a systematic review on extrapulmonary intrathoracic blastomycosis, focusing on mediastinal involvement.

Case report
In January 2014, an 18-year-old female with a past medical history only significant for asthma presented with lymphadenopathy to the University of Chicago Emergency Department.Her symptoms began 2 weeks prior to admission and included intermittent fevers, chills, night sweats and multiple enlarging masses in the cheeks and neck.Her review of systems was notable for a mild, non-productive cough and an unintentional 20-pound weight loss during the previous 2 months.She denied sick contacts, exposure to tuberculosis, recent travel outside of the Chicago area, history of mononucleosis, contact with animals, insect bites, frequent infections or sexual activity.Her family history was unremarkable.She denied use of tobacco, alcohol and recreational drugs.After she failed to respond to a 5-day course of cephalexin, her primary care physician referred her to the Emergency Department.
On physical examination, she appeared well with no cachexia or wasting.Her temperature was 39.1 u C, heart rate 115 beats min 21 , respiratory rate 20 breaths min 21 , blood pressure 115/76 mmHg and oxygen saturation 98 % on room air.She had masses palpable in the neck and shoulders, presumed to be extensive lymphadenopathy, including a 264 cm right supraclavicular node, a 162 cm right submandibular node and a 161 cm submental node.She had no palpable axillary or inguinal lymphadenopathy.There was a 563 cm firm and tender left parotid mass.She had moist mucus membranes, the oropharynx was without erythema, tonsillar enlargement or exudates, and the cranial nerve examination was normal.A cardiac examination demonstrated tachycardia with normal heart sounds and no murmur, gallop or pericardial rub.The lung sounds were normal with no crackles or wheezing.The abdomen was benign with no palpable hepatosplenomegaly or masses.She had no rash or stigmata of endocarditis.Her extremities showed a full range of motion with no clubbing, cyanosis or oedema.The neurological examination was non-focal.
Given the concern for malignancy or a disseminated infectious process, she was admitted to the hospital for further work-up.Initial laboratory work revealed a granulocyte-predominant leukocytosis of 14.2610 3 ml 21 (80 % granulocytes, 12 % lymphocytes, 6 % monocytes, 2 % eosinophils, no blasts), microcytic anaemia of 8.6 g dl 21 with a mean corpuscular volume of 65 %, and a normal platelet count of 449610 3 ml 21 .Her basic metabolic panel, liver function tests and urinalysis were normal.An electrocardiogram demonstrated normal sinus rhythm, normal axis, normal intervals and non-specific T-wave inversions in leads V1-V6.Routine bacterial blood cultures were negative, and testing for syphilis (rapid plasma reagin), human immunodeficiency virus (ELISA), Mycobacterium tuberculosis (IFN-c release assay), serologies for hepatitis B, hepatitis C, Bartonella and parvovirus (IgM/IgG), and urine Legionella pneumophila antigen were all negative.A urine Histoplasma antigen test, Blastomyces serologies and Coccidioides immitis serologies were also sent.
On hospital day 1, a computed tomography (CT) scan of the head and neck revealed extensive cervical lymphadenopathy with cystic/necrotic changes extending into the upper mediastinum, as well as many cystic/necrotic lesions within the musculature and subcutaneous tissues of the neck.A CT scan of the chest, abdomen and pelvis demonstrated a 206669 cm heterogenous mediastinal mass with extension into the right hilum, a small pericardial effusion and several ill-defined splenic lesions (Figs. 1 and 2).These findings raised concern for lymphoma or thymic malignancy.
On hospital day 2, she underwent an excisional biopsy of the enlarged right supraclavicular lymph node.Microscopic pathological evaluation demonstrated mixed granulomatous and acute inflammation with focal necrosis.Thickwalled budding yeasts were later reported both within multinucleated giant cells and extracellularly.There was no evidence of malignancy.On hospital day 5, the Blastomyces serum antibody result was positive, and therapy with intravenous liposomal amphotericin B at 3 mg kg 21 every 24 h was initiated.Given the rarity of blastomycosis presenting as a mediastinal mass and persistent concern for lymphoma or thymic malignancy, an interdisciplinary team including physicians from the oncology, infectious disease, otolaryngology and thoracic surgery services recommended a biopsy by video-assisted thorascopic surgery (VATS) to confirm the diagnosis of blastomycosis and to assess for evidence of malignancy.
On hospital day 6, a VATS biopsy of the mediastinal mass was performed.The pathology evaluation revealed acute and chronic inflammation with poorly formed granulomata and budding fungal yeast forms with spherical refractile walls (periodic acid-Schiff stain positive, Gomori methenamine silver stain positive, mucicarmine negative) (Figs. 3  and 4), consistent with blastomycosis.After 3 weeks, cultures from the biopsy of the supraclavicular node and the VATS biopsy specimen both grew B. dermatitidis.The patient recovered uneventfully from the procedure and was discharged to home with a 2-week course of intravenous liposomal amphotericin B 3 mg kg 21 every 24 h followed by a plan for at least 1 year of itraconazole 200 mg twice daily with meals.At her 1-month outpatient follow-up appointment, her liver function tests remained normal, the lymphadenopathy had resolved and she felt well again.

Methods
We performed a systematic review of the literature with a PubMed search for the keywords 'blastomycosis OR blastomyces OR Gilchrist's disease', limited to the English language and published prior to 19 August 2014.This search  resulted in 2614 citations.Studies were selected for further review if they described a human infection with B. dermatitidis and included the words 'disseminated', 'miliary', 'systemic', 'mediastinal', 'pleural' or 'pulmonary', or if they did not explicitly identify the involved organ systems.These criteria were fulfilled by 298 citations, which were then retrieved and reviewed in full text.The titles of references cited in the papers identified in the PubMed search were reviewed, and an additional seven papers not indexed in PubMed were identified for inclusion in this review.In total, our review of published reports yielded 24 relevant cases of mediastinal blastomycosis.The 25 cases, including the one described in the present report, are shown in Table 1.

Discussion
This systematic review confirmed our impression that mediastinal disease is a rare manifestation of blastomycosis.It also demonstrates the importance of timely and appropriate antifungal therapy, as the rate of survival increased from 7 to 88 % when patients received amphotericin B or an azole antifungal agent.The only patient to die after receiving amphotericin B did not receive it until late in the course of his disease (Alhaji & Sadikot, 2013), emphasizing the importance of early diagnosis and initiation of antifungal therapy.
In a patient presenting with mediastinal mass, a broad infectious disease differential diagnosis should be considered (Table 2).Abscesses caused by Staphylococcus aureus have been reported in the mediastinum in the absence of recent surgery but only in high-risk cases, such as intravenous drug users or patients on haemodialysis (Nwiloh et al., 2000;Pe ´rez-Cardona et al., 2008;Salata, 1987).Descending neck infections may be a sequela of oropharyngeal infection, as in Lemierre's syndrome, although this usually presents with severe pain from pharyngitis and progresses to sepsis from infected thrombosis of the internal jugular vein.Tuberculosis, which is frequently associated with widespread lymphadenopathy and can involve the mediastinum, is now rare in the USA, particularly in the absence of known high-risk travel or exposures.Non-tuberculous mycobacterial infections are rare in young immunocompetent adults, although there have been cases of disseminated BCG-osis following vaccination outside the USA (Ying et al., 2014).Toxoplasmosis typically occurs in immunocompromised hosts, but it has been reported as a cause of mediastinal lymphadenopathy in a child (el-Naggar et al., 1971).Bartonellosis and tularaemia are often associated with lymphadenopathy but not with mediastinal masses, and both occur after specific exposures.Nocardiosis with mediastinal involvement has been reported rarely (Kroe et al., 1997;Wang et al., 2010).Mediastinal actinomycosis is also rare but has been reported in children as a mimic of malignancy (Ng et al., 1992).Multiple cases of histoplasmosis presenting as a mediastinal mass have been observed (Camacho et al., 1996;Rose et al., 2008;Shersher et al., 2012), as well as mediastinal fibrosis without identification of the organism (Landay & Rollins, 1989;Loyd et al., 1988).Similarly, the literature on coccidiomycosis includes multiple cases of mediastinal adenopathy (Diaz et al., 1991;Stephany et al., 2005) and pericarditis (Arsura et al., 2004).
The apparent rarity of mediastinal blastomycosis observed here deserves further note, as Baker & Brian (1937) described cardiac blastomycosis as 'comparatively frequent' after nine cases were diagnosed between 1904 and 1936.During 80 years since 1936, only 14 cases with mediastinal involvement have been reported in the literature.This declining incidence may be attributed to the prevention of advanced disease by greater awareness in endemic areas leading to earlier diagnosis and the advent of effective antifungal therapies.It should be noted that many early cases were only diagnosed at autopsy, a practice in persistent decline over the past century, perhaps resulting in a greater number of undetected or missed cases (Shojania & Burton, 2008).
Whilst blastomycosis affected the pleura in more than onethird of cases in our review, this has previously been described as 'rare' (Jay et al., 1977) and recently as 'uncommon' (Wiesman et al., 1999).Early radiographic studies estimated the incidence of effusion at 2-7 % (Abernathy, 1959;Kaplan & Clifford, 1964) and pleural thickening at 33 % (Abernathy, 1959) of cases of pulmonary blastomycosis.Later studies with presumably more sensitive radiographic studies reported effusions in 15-21 % (Kinasewitz et al., 1983;Sheflin et al., 1990) and pleural thickening in as many as 88 % of patients (Kinasewitz et al., 1983).More recently, CT has identified effusions in 13-26 % and some degree of pleural thickening or reaction in 15-25 % (Ronald et al., 2009;Winer-Muram et al., 1992).The incidence of pleural involvement in our series was probably inflated by the advanced stages of disease at the times of diagnosis.If Blastomyces or a broad-based budding yeast consistent with Blastomyces is observed on culture or pathology from a lymph node biopsy in a patient similar to the one in our report, we believe that this would be an indication for immediate antifungal therapy.However, in the case described in the present report, the plan for the VATS was made on the day of the lymph node biopsy.The concern for malignancy was so great that the VATS was performed before the final results from the lymph node biopsy were reported, which ultimately showed positive stains for the yeast.
In conclusion, almost all mediastinal masses should be biopsied to rule out malignancy, but a broad infectious differential that includes blastomycosis should also be considered.Whilst mediastinal blastomycosis remains a rare manifestation of extrapulmonary disease, it has a high risk of death when untreated and responds readily to timely and appropriate therapy.

Fig. 1 .
Fig. 1.CT scan of the chest with contrast demonstrating a 2066.268.8 cm heterogeneous mass with extension into the right hilum.

Fig. 2 .
Fig. 2. CT scan of the chest with contrast, demonstrating a mediastinal mass in a coronal reconstruction.

Fig. 3 .
Fig. 3. Histological section of the mediastinal lymph node showing a multinucleated giant cell with thick-walled budding yeasts.Note neutrophils in the background.Haematoxylin and eosin stain; original magnification 6400.

Table 1 .
Demographic characteristics, clinical presentation, therapy, and outcome of 25 patients with mediastinal blastomycosis reported in the published literature, 1904-

Table 2 .
Infectious differential diagnosis of supraclavicular lymphadenopathy and a mediastinal mass Drawn from case series; data may be limited.