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Histoplasmomas of Uncommon SizeHistoplasmomas of Uncommon Size FREE TO VIEW

Bradley W. Richmond, MD; John A. Worrell, MD; Julie A. Bastarache, MD; Daniel H. Gervich, MD; Wendolyn R. Slattery, MD; James E. Loyd, MD
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From the Division of Allergy, Pulmonary, and Critical Care Medicine (Drs Richmond, Bastarache, and Loyd) and the Department of Radiology (Dr Worrell), Vanderbilt University School of Medicine, Nashville, TN; CIC Associates (Dr Gervich), Mercy Medical Center, Des Moines, IA; and Mercy Hospital (Dr Slattery), Allina Hospitals and Clinics, Coon Rapids, MN.

Correspondence to: Bradley W. Richmond, MD, Vanderbilt University Medical Center, Division of Allergy, Pulmonary, and Critical Care Medicine, B1323 Vanderbilt Medical Center North, 1161 21st Ave S, Nashville, TN 37232; e-mail: bradley.richmond@vanderbilt.edu


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Chest. 2013;143(6):1795-1798. doi:10.1378/chest.12-2071
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Histoplasma capsulatum infection demonstrates a broad spectrum of acute and chronic clinical manifestations. Unlike the acute reaction to proliferating organisms, the chronic complications are often the result of excessive or prolonged host response with a paucity of organisms. Lung nodules (histoplasmomas) may be noted decades after initial infection and present a challenging clinical problem, as they can be difficult to distinguish from malignancy or tuberculomas. Typically, histoplasmomas are small (<1 cm), asymptomatic, and may be stable in size or slowly enlarge over time. Here we report three patients with unusually large, or giant, histoplasmomas (>3 cm) and describe their extreme phenotype. Importantly, two of the patients presented with subacute symptomatic disease, a presentation that is very atypical for histoplasmoma. The term “buckshot” calcification has been used to describe dozens of small (2-4 mm) calcified nodules, so it may be appropriate to label masses that exceed 3 cm as “cannonball” histoplasmoma.

Figures in this Article

Histoplasma capsulatum is a dimorphic fungus found throughout the world, with particularly high seroprevalence rates in the Ohio and Mississippi River Valleys of the United States.1 With rare exceptions, infection results from inhalation of spores. Although the majority of exposures do not lead to significant disease, a variety of pulmonary manifestations have been described depending on degree of exposure, immune status of the host, and presence or absence of structural lung disease.2 Initial infection may be asymptomatic or result in acute or subacute pneumonia with or without mediastinal adenitis. As the disease resolves, focal areas of infiltrate may coalesce to form nodules that slowly enlarge and calcify over time. Prior to their initial description by Puckett3 in 1953, these “histoplasmomas” were frequently mistaken for malignant tumors or tuberculomas.

In 1969, Goodwin and Snell4 reported a series of 17 patients with surgically resected histoplasmomas that ranged in size from 8 to 35 mm. Eight patients in the series had serial imaging over a period of 25 to 116 months, and among these patients the average rate of increase in diameter was just under 2 mm/y.4 Here we describe three patients who developed multiple, unusually large histoplasmomas, which to our knowledge has not been previously reported.

Case 1

An 18-year-old man from Ohio had an abnormality detected on a routine chest radiograph while serving at Guantanamo Bay Naval Base, Cuba, in 1951. At the time of the examination he had no respiratory symptoms, was able to participate in military training and recreational sports, and did not use tobacco. He was transferred to the US Naval Hospital in Portsmouth, Virginia, where it was determined he did not have TB, and he continued military service until 1956. Following discharge he began work as a project engineer at a manufacturing firm. He was again noted to have an abnormal chest radiograph, and because of concern for malignancy he underwent partial resection of the left lower lobe. He was told that he had histoplasmosis, but no treatment was recommended. For the next 3 decades he maintained an active lifestyle and had no respiratory complaints. He moved to Tennessee following retirement in 1995 and began to note dyspnea during exertion. In 1998 he sought medical evaluation, and chest radiography showed calcified mediastinal, bilateral lower lobe, and right middle lobe masses ranging up to 7.7 cm in diameter (Fig 1A). Pulmonary function testing revealed severe obstructive lung disease, with FEV1 of 1.69 L (45% predicted). Bronchoscopy revealed no airway obstruction. Serologic testing for aspergillosis, blastomycosis, coccidiomycosis, and histoplasmosis was negative, as was urine Histoplasma antigen testing. From 2000 to 2007, the FEV1 decreased by 310 mL, but none of the calcified masses increased in size (Fig 1B).

Figure Jump LinkFigure 1. A, Case 1. Posterior-anterior chest radiograph from 1998 shows multiple calcified mediastinal, bilateral lower, and right middle lobe masses up to 7.7 cm in diameter. B, Case 1. Masses are unchanged in size on posterior-anterior chest radiograph from 2007. C, Case 2. Soft-tissue window from contrasted CT scan of the chest in 2003 shows a complex soft-tissue mass (average attenuation 30.34 Hounsfield units) with internal septations extending from the subcarinal region to right paraesophageal region and measuring 4.9×4.0 cm in maximal diameter. D, Case 2. By 2011, the right paratracheal and paraesophageal masses have coalesced to form a mixed matrix consisting of calcium and soft-tissue attenuation. Some of the other parenchymal nodules increased in size, and others decreased. E, Case 3. Lung windows from contrasted CT scan of the chest in 2011 show multiple noncalcified pulmonary nodules with a right middle lobe mass measuring 3.5×2.9 cm. F, Case 3. Repeat contrasted CT from 2012 showed no change in the size of the right middle lobe mass, but several other nodules have appeared or increased in size.Grahic Jump Location
Case 2

A 12-year-old girl from Iowa presented in 2003 with right-sided neck and shoulder pain, chest pain, and dyspnea on exertion. Contrasted CT scan of the chest showed a 4.9×4.0 cm complex soft tissue mass with internal septations extending from the subcarinal region to the right paraesophageal region (Fig 1C) and a 3.4×3.3 cm right paratracheal mass with mixed calcified and soft-tissue attenuation. The paraesophageal mass pressed upon the left atrium, and a small pericardial effusion was present. Calcified right lobar, right interlobar, and left lobar lymph nodes were up to 2.2 cm in short-axis diameter. Also noted were multiple calcified nodules in the right lower lobe, left upper lobe, and left lower lobe.

Pericardiocentesis and transthoracic needle aspiration of the subcarinal mass were nondiagnostic, so the patient underwent exploratory thoracotomy with decortication, excisional biopsy of a right paratracheal lymph node, and wedge biopsy of the right lower lobe. Pathologic examination revealed necrotizing granulomas and fungal forms suspicious for H capsulatum (Fig 2A, 2B). Stains and cultures for bacterial, fungal, and acid-fast pathogens were negative. Acute complement fixation titers for Histoplasma revealed phase 1 (mycelial) and phase 2 (yeast) titers of 1:8, and convalescent titers demonstrated a rise in phase 1 titer to 1:32 and rise in phase 2 titer to 1:64. Immunodiffusion testing revealed positive M and H bands. Amphotericin B was administered in the hospital followed by itraconazole at home. Nine months later the patient was found to have an enlarging tender mass on the right side of her neck and worsening dyspnea. CT scan showed an enlarged, necrotic lymph node inferior to the right submandibular gland and, in the chest, enlarging fluid collections in the right azygoesophageal recess and adjacent to the left heart border, with possible extension into the pericardial space. Amphotericin B was initiated, and repeat thoracotomy with drainage of the left hilar fluid collection and partial left pericardiectomy was performed. Amphotericin B was continued for several months followed by voriconazole, but eventually the right-sided neck swelling recurred and was accompanied by painful swelling in the subxiphoid region. A right cervical lymph node and abdominal wall abscess were resected and again showed necrotizing granulomas and yeast forms suspicious for histoplasmosis. She was referred to a tertiary care center, where a workup for immunodeficiency was reportedly unrevealing.

Figure Jump LinkFigure 2. A, Case 2. Hematoxylin and eosin staining of lung parenchyma and pleura shows necrotizing granulomatous inflammation (original magnification ×100). B, Case 2. Silver (GMS) stain shows a budding yeast form consistent with Histoplasma (black arrow, original magnification ×1,000). C, Case 3. Silver (GMS) stain shows numerous fungal forms consistent with Histoplasma (black arrows, original magnification ×600).Grahic Jump Location

Despite long-term treatment with a variety of antifungals, over the next few years the patient required thoracotomy and resection of a left lung abscess (2005), resection of a midline neck mass (2006), and percutaneous drainage of a paraesophageal abscess (2009). Neither Histoplasma nor any bacterial pathogens were cultured from any of these specimens. Prevotella and group C Streptococcus were isolated from a right upper lobe abscess that was drained percutaneously in 2008 and 2011 and were believed to represent postobstructive pneumonia due to extrinsic compression of the right upper lobe bronchus. Repeat CT scan from May 7, 2011, showed that the right paratracheal mass had increased in size, the paraesophageal mass had remained stable in size, and some of the calcified nodules had increased in size while others regressed (Fig 1D).

Case 3

A 60-year-old woman from rural Minnesota developed severe nonproductive cough in early 2011. She was a kindergarten teacher, used no tobacco products, and apart from the cough had no respiratory complaints, fever, or chills. She underwent contrasted CT imaging of the chest, which showed a 3.5×2.9 cm right middle lobe mass, numerous noncalcified parenchymal nodules, and enlarged, noncalcified right paratracheal, subcarinal, and right interlobar lymph nodes (Fig 1E). After an initial percutaneous CT scan-guided biopsy was nondiagnostic, she was referred to a center in Minnesota experienced in the diagnosis and management of histoplasmosis. Here a percutaneous fine-needle aspiration with core biopsies showed necrotizing granulomas and yeast forms consistent with H capsulatum (Fig 2C). Complement fixation testing for Histoplasma antibodies, confirmed by immunodiffusion, was positive. Treatment with itraconazole was initiated. A CT scan obtained 3 months later showed no interval change, and so an open-lung biopsy of two left lower lobe nodules was performed. Pathology from these lesions also showed necrotizing granulomas, although stains and cultures for fungal and acid-fast bacilli organisms were negative. The patient’s cough eventually resolved, and itraconazole was discontinued after 5 months because of the development of a rash. A repeat chest CT from April 4, 2012, showed the enlarged lymph nodes and right middle lobe mass to be stable in size, whereas many of the noncalcified parenchymal nodules had increased in size (Fig 1F).

This report of three patients with very large histoplasmomas extends the already broad range of disease manifestations associated with H capsulatum and demonstrates that histoplasmomas may rarely be associated with substantial morbidity. In addition, giant histoplasmomas can present as either subacute or chronic mass lesions and may be associated with significant respiratory or systemic symptoms. In the subacute forms (cases 2 and 3), the diagnosis of histoplasmoma was made by direct visualization of the organism in biopsy specimens, whereas in the chronic, asymptomatic form (case 1) the patient was told Histoplasma was seen, but the pathology testing results are no longer available. A Histoplasma urinary antigen enzyme immunoassay is now available to aid in the diagnosis of histoplasmosis but was negative for both patients who underwent testing despite that fact that organisms were demonstrated on biopsy. Immunocompetent patients with subacute disease likely have a low pathogen burden, which may contribute to the low sensitivity of the test in this population.5 Both patients who had serologic testing for histoplasmosis had mildly positive results. Given the high seroprevalence rates in endemic areas, a positive serologic test alone does not have sufficient positive predictive value to avoid biopsy, particularly given that malignant tumors and tuberculomas may be radiographically similar to histoplasmomas. A variety of radiographic criteria may help distinguish histoplasmomas from malignancy, but none are sufficiently sensitive or specific to preclude biopsy in high-risk patients.6 In the right clinical setting however, repeated biopsies are unnecessary and may lead to additional complications, such as bacterial superinfection. Coccidioides immitis may also lead to coin lesions, but there are only a few areas where the habitats of the two organisms overlap.1,7 Because histoplasmomas are usually of little clinical significance, specific treatment is unnecessary after the diagnosis is established. Although it is unclear how patients with “cannonball” histoplasmomas should be managed, the patients in cases 2 and 3 had little objective clinical response to antifungal therapy, and it is our opinion that antifungal and/or systemic steroid therapy is unlikely to be of significant benefit.

It is not presently known whether the initiation and maintenance of histoplasmomas depends upon pathogen virulence factors, the host response, or a combination of both. Patients who develop adenitis as part of acute infection sometimes develop mass-like structures called mediastinal granulomas, which consist of semiliquid material covered by a thin fibrotic capsule. These lesions are usually of no clinical significance. Rarely, these lymph nodes may become involved in a fibrotic, locally invasive process that may result in death from compression of the major vessels of the mediastinum (fibrosing mediastinitis).8 In a similar manner, typical histoplasmomas may result from altered local immune responses to infection in the lung parenchyma, and very rarely host factors lead to the formation of giant histoplasmomas in the lung parenchyma. It is not known why some patients develop complications of histoplasmosis in the lung parenchyma and others develop problems in the mediastinum, but it may relate to where organisms are most prevalent during the initial infection. Further studies should examine differences in the host response between patients who develop late complications of histoplasmosis, such as giant histoplasmomas and fibrosing mediastinitis, and those who resolve their disease.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors obtained patient permission to publish this information.

Edwards LB, Acquaviva FA, Livesay VT. Further observations on histoplasmin sensitivity in the United States. Am J Epidemiol. 1973;98(5):315-325. [PubMed]
 
Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore). 1981;60(4):231-266. [PubMed]
 
Puckett TF. Pulmonary histoplasmosis; a study of twenty-two cases with identification ofH. capsulatumin resected lesions. Am Rev Tuberc. 1953;67(4):453-476. [PubMed]
 
Goodwin RA Jr, Snell JD Jr. The enlarging histoplasmoma. Concept of a tumor-like phenomenon encompassing the tuberculoma and coccidioidoma. Am Rev Respir Dis. 1969;100(1):1-12. [PubMed]
 
Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53(5):448-454. [CrossRef] [PubMed]
 
Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med. 2004;25(2):129-144. [CrossRef] [PubMed]
 
Kirkland TN, Fierer J. Coccidioidomycosis: a reemerging infectious disease. Emerg Infect Dis. 1996;2(3):192-199. [CrossRef] [PubMed]
 
Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore). 1988;67(5):295-310. [PubMed]
 

Figures

Figure Jump LinkFigure 1. A, Case 1. Posterior-anterior chest radiograph from 1998 shows multiple calcified mediastinal, bilateral lower, and right middle lobe masses up to 7.7 cm in diameter. B, Case 1. Masses are unchanged in size on posterior-anterior chest radiograph from 2007. C, Case 2. Soft-tissue window from contrasted CT scan of the chest in 2003 shows a complex soft-tissue mass (average attenuation 30.34 Hounsfield units) with internal septations extending from the subcarinal region to right paraesophageal region and measuring 4.9×4.0 cm in maximal diameter. D, Case 2. By 2011, the right paratracheal and paraesophageal masses have coalesced to form a mixed matrix consisting of calcium and soft-tissue attenuation. Some of the other parenchymal nodules increased in size, and others decreased. E, Case 3. Lung windows from contrasted CT scan of the chest in 2011 show multiple noncalcified pulmonary nodules with a right middle lobe mass measuring 3.5×2.9 cm. F, Case 3. Repeat contrasted CT from 2012 showed no change in the size of the right middle lobe mass, but several other nodules have appeared or increased in size.Grahic Jump Location
Figure Jump LinkFigure 2. A, Case 2. Hematoxylin and eosin staining of lung parenchyma and pleura shows necrotizing granulomatous inflammation (original magnification ×100). B, Case 2. Silver (GMS) stain shows a budding yeast form consistent with Histoplasma (black arrow, original magnification ×1,000). C, Case 3. Silver (GMS) stain shows numerous fungal forms consistent with Histoplasma (black arrows, original magnification ×600).Grahic Jump Location

Tables

References

Edwards LB, Acquaviva FA, Livesay VT. Further observations on histoplasmin sensitivity in the United States. Am J Epidemiol. 1973;98(5):315-325. [PubMed]
 
Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore). 1981;60(4):231-266. [PubMed]
 
Puckett TF. Pulmonary histoplasmosis; a study of twenty-two cases with identification ofH. capsulatumin resected lesions. Am Rev Tuberc. 1953;67(4):453-476. [PubMed]
 
Goodwin RA Jr, Snell JD Jr. The enlarging histoplasmoma. Concept of a tumor-like phenomenon encompassing the tuberculoma and coccidioidoma. Am Rev Respir Dis. 1969;100(1):1-12. [PubMed]
 
Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53(5):448-454. [CrossRef] [PubMed]
 
Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med. 2004;25(2):129-144. [CrossRef] [PubMed]
 
Kirkland TN, Fierer J. Coccidioidomycosis: a reemerging infectious disease. Emerg Infect Dis. 1996;2(3):192-199. [CrossRef] [PubMed]
 
Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore). 1988;67(5):295-310. [PubMed]
 
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