- Email: [email protected]
Latent Enigma
The American Journal of Medicine (2006) 119, 581-583
IMAGES IN RADIOLOGY Michael Bettmann, MD, Section Editor
Latent Enigma Divay Chandra, MD, Babith J. Manikdiyil, MD, Elizabeth Guy, MD, Richard J. Hamill, MD Department of Medicine, Baylor College of Medicine, Houston, Tex.
PRESENTATION
DIAGNOSIS
A 28-year-old Hispanic female presented with a 1-month history of pain and swelling in the left arm. There was no preceding trauma to the arm, and she denied fever, cough, shortness of breath, or weight loss. Her vital signs on presentation were normal, and the only notable finding on physical examination was pitting edema extending from the left hand to the shoulder, without any warmth or erythema. She moved to Texas from Mexico at the age of 15 years.
The patient was diagnosed with mediastinal fibrosis due to histoplasmosis. To the best of our knowledge, this is the first reported case of isolated left brachiocephalic vein involvement at presentation. Mediastinal fibrosis is a rare disease resulting from uncontrolled proliferation of fibrous tissue in the mediastinum. It is also known as fibrosing mediastinitis and sclerosing mediastinitis.1 In the United States, mediastinal fibrosis most commonly occurs as a highly unusual—and very dangerous—sequela of primary infection with the fungus H. capsulatum, though the mechanism by which this occurs is debated.2-3 More infrequent causes include infection with Mycobacterium tuberculosis or Blastomyces dermatitidis, Behçet’s syndrome, sarcoidosis, radiation therapy, Riedel’s thyroiditis, sclerosing cholangitis, and methysergide use. When no specific cause can be identified, the fibrosis is said to be idiopathic. Typically, the histopathological examination reveals abundant, paucicellular fibrosis with obliteration of adipose tissue. In 2 studies of mediastinal fibrosis due to histoplasmosis, 54% (27/49) and 45% (9/18) of biopsies showed the organism on staining.2,4 Patients present years after a subclinical primary infection with H. capsulatum, frequently in the second to fourth decades of life.2 Most develop symptoms due to involvement of mediastinal structures, usually the airway, which can result in cough (41%), dyspnea (32%), hemoptysis (31%) or pneumonia (23%).2 Involvement of other structures can result in the superior vena cava syndrome (6%); dyspnea and hemoptysis due to compression of the pulmonary veins; pulmonary hypertension and cor pulmonale due to pulmonary artery compression; hoarseness due to recurrent laryngeal nerve involvement (2%); dysphagia (2%) and upper gastrointestinal bleeding due to esophageal involvement; and angina due to encasement of the aorta and its branches.2,5 Aside from the aforementioned signs and symptoms, findings on physical examination rarely add any additional diagnostic information. Most commonly, plain radiography of the chest will indicate the presence of a hilar mass (39%), parenchymal opacities (30%), and widening of the medias-
ASSESSMENT The patient’s white blood cell count, serum chemistries, and liver enzymes were unremarkable. A Doppler ultrasound confirmed the presence of deep vein thrombosis in the affected arm. Mediastinal widening with a small infiltrate in the left upper lung was evident in an initial radiograph (Figures 1 and 2). The infiltrate adjoined a 3⫻8 cm mass in the anterior mediastinum that was compressing the left brachiocephalic vein, according to a computed tomograpy (CT) scan (Figures 3 and 4). Blood tests for HIV, antinuclear antibody, and rheumatoid factor were negative, as was a urine test for Histoplasma polysaccharide antigen. Bronchoscopy, done to evaluate the left upper lobe, showed normal airways; culture and staining, including an acid-fast stain, of lavage samples were negative for fungi and bacteria. Four transbronchial biopsies from the same region were unremarkable. A CT-guided biopsy of the mediastinal mass showed fibrosis with spindle cells. Thoracotomy was performed, and the surgical biopsy specimen showed diffuse fibrosis, with granulation tissue and vascular proliferation. There was no evidence of malignancy, and no acid-fast bacilli or granulomas were seen. The Gomori methenamine silver stain displayed extracellular yeast forms, 2 to 4 microns in diameter, compatible with the fungus Histoplasma capsulatum (Figure 5). Requests for reprints should be addressed to Divay Chandra, MD, Department of Internal Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail address: [email protected]
0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.05.020
582
The American Journal of Medicine, Vol 119, No 7, July 2006
Figure 1 The initial chest radiograph (posterio-anterior view) showed widening of the mediastinum with a small infiltrate in the left upper lung.
tinum (28%).2 Occasionally, pulmonary artery enlargement, cardiomegaly, pleural effusion, and lung volume loss are noted.2 CT scans confirm the presence of a mass and provide detailed information about the extent of involvement of mediastinal structures. Currently, magnetic resonance imaging offers no advantage over CT in diagnosis or in defining the status of mediastinal structures.1 Establishing the diagnosis can be quite difficult and generally requires a surgical procedure. Tumors such as Hodgkin’s lymphoma, which can cause extensive fibrosis, cannot be ruled out with confidence on the smaller biopsy specimens obtained by minimally invasive techniques. Identifying the underlying cause for the mediastinal fibrosis
Figure 2
This is the lateral view.
Figure 3 An infiltrate in the left upper lobe was also visible on the first computed tomography (CT) scan with contrast. The right brachiocephalic vein (1), the brachiocephalic artery (2), the left common carotid (3), and the left subclavian artery (4) can be seen as well.
can be challenging as well. When infections are responsible, the usual markers are absent because the acute phase of the infection resolved many years prior to presentation. In one series by Loyd et al, 65% of cases (22/34) had a positive serum complement fixation test, defined as a titer greater than 1:32, at diagnosis.2 Notably, the test was negative in the remaining 35% (12/34), who had either histology or cultures positive for H. capsulatum. No data exists on the sensitivity or specificity of the urine Histoplasma antigen test; however, we do not expect it to be particularly useful because of the remoteness of the acute infection.
Figure 4 The CT scan delineated a retrosternal mass (1), the right brachiocephalic vein (2) at the level of the junction (3) with the left brachiocephalic vein, and the upper part of the arch of the aorta (4).
Chandra et al
583 et al, 21 of 71 patients (30%) died; 9 of these deaths were perioperative.2 Another study reported a mortality rate of 20%, with all the deaths occurring in the perioperative period.4 It is unclear how the availability of the new minimally invasive techniques would affect this high mortality rate. Our patient started a 3-month course of itraconazole and a warfarin regimen. Her arm swelling improved with anticoagulation, and the mass remained radiologically stable over 7 months of follow up.
ACKNOWLEDGEMENTS:
Figure 5 Gomori methenamine silver staining (⫻400) of surgically-obtained mediastinal tissue showed ovoid extracellular yeast (arrow), 2-4 m in diameter with narrow-based budding (H. capsulatum).
Ordinarily, the definitive diagnosis would be made when cultures are positive, or the organism is seen on pathology, as mentioned previously.
MANAGEMENT Treatment options are few, and their efficacy is limited. Alternatives include anti-inflammatory and antifungal agents, and procedures to salvage the involved mediastinal structures. Anti-inflammatory treatment with corticosteroids has not proven to be of any benefit.6,7 Antifungal treatment with the azole drugs is controversial. Itraconazole is considered the drug of choice for H. capsulatum infection and may have some role when features of ongoing or recurrent infection are present in the form of fever and other systemic symptoms.4,8 Treatment for symptomatic involvement of the central vasculature and airways has traditionally involved open surgical resection and reconstruction. These surgeries are technically challenging due to the dense fibrosis in the mediastinum, and as a result, they are associated with high perioperative mortality (up to 20%).4 Newer minimally invasive procedures are being developed, including endoluminal stenting of vascular structures and bronchoscopic stenting of compressed airways.9-11 Survival is difficult to estimate due to the small volume of data and lack of adequate follow up. In the series by Loyd
We would like to acknowledge Bobby L Boyanton, MD, Department of Pathology, Baylor College of Medicine, Houston, Tex, for assistance with histopathology, and Joan Hacken, MD, Department of Radiology, Baylor College of Medicine and Michael E. DeBakey, MD, Veterans Affairs Medical Center, Houston, Tex, for assistance with the radiology images.
References 1. Rossi SE, McAdams HP, Rosado-de-Christenson ML, Franks TJ, Galvin JR. Fibrosing mediastinitis. Radiographics. 2001;21:737-757. 2. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore). 1988;67:295-310. 3. Schowengerdt CG, Suyemoto R, Main FB. Granulomatous and fibrous mediastinitis. A review and analysis of 180 cases. J Thorac Cardiovasc Surg. 1969;57:365-379. 4. Mathisen DJ, Grillo HC. Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg. 1992;54:1053-1058. 5. Holman WL, Sethi GK, Scott SM. Coronary artery bypass grafting with unanticipated fibrosing mediastinitis. Ann Thorac Surg. 1990;49: 321-322. 6. Gran JT. Chronic idiopathic mediastinal fibrosis presenting with malaise, pleuritis and thoracic back pain. Br J Rheumato. 1993;32:757759. 7. Dines DE, Payne WS, Bernatz PE, Pairolero PC. Mediastinal granuloma and fibrosing mediastinitis. Chest. 1979;75:320-324. 8. Maholtz MS, Dauber JH, Yousem SA. Case report: fluconazole therapy in histoplasma mediastinal granuloma. Am J Med Sci. 1994;307: 274-277. 9. Doyle TP, Loyd JE, Robbins IM. Percutaneous pulmonary artery and vein stenting: a novel treatment for mediastinal fibrosis. Am J Respir Crit Care Med. 2001;164:657-660. 10. Fontaine AB, Borsa JJ, Hoffer EK, Bloch RD, So C. Stent placement in the treatment of pulmonary artery stenosis secondary to fibrosing mediastinitis. J Vasc Interv Radiol. 2001;12:1107-1111. 11. Watkinson AF, Hansell DM. Expandable Wallstent for the treatment of obstruction of the superior vena cava. Thorax. 1993;48:915-920.
IMAGES IN RADIOLOGY Michael Bettmann, MD, Section Editor
Latent Enigma Divay Chandra, MD, Babith J. Manikdiyil, MD, Elizabeth Guy, MD, Richard J. Hamill, MD Department of Medicine, Baylor College of Medicine, Houston, Tex.
PRESENTATION
DIAGNOSIS
A 28-year-old Hispanic female presented with a 1-month history of pain and swelling in the left arm. There was no preceding trauma to the arm, and she denied fever, cough, shortness of breath, or weight loss. Her vital signs on presentation were normal, and the only notable finding on physical examination was pitting edema extending from the left hand to the shoulder, without any warmth or erythema. She moved to Texas from Mexico at the age of 15 years.
The patient was diagnosed with mediastinal fibrosis due to histoplasmosis. To the best of our knowledge, this is the first reported case of isolated left brachiocephalic vein involvement at presentation. Mediastinal fibrosis is a rare disease resulting from uncontrolled proliferation of fibrous tissue in the mediastinum. It is also known as fibrosing mediastinitis and sclerosing mediastinitis.1 In the United States, mediastinal fibrosis most commonly occurs as a highly unusual—and very dangerous—sequela of primary infection with the fungus H. capsulatum, though the mechanism by which this occurs is debated.2-3 More infrequent causes include infection with Mycobacterium tuberculosis or Blastomyces dermatitidis, Behçet’s syndrome, sarcoidosis, radiation therapy, Riedel’s thyroiditis, sclerosing cholangitis, and methysergide use. When no specific cause can be identified, the fibrosis is said to be idiopathic. Typically, the histopathological examination reveals abundant, paucicellular fibrosis with obliteration of adipose tissue. In 2 studies of mediastinal fibrosis due to histoplasmosis, 54% (27/49) and 45% (9/18) of biopsies showed the organism on staining.2,4 Patients present years after a subclinical primary infection with H. capsulatum, frequently in the second to fourth decades of life.2 Most develop symptoms due to involvement of mediastinal structures, usually the airway, which can result in cough (41%), dyspnea (32%), hemoptysis (31%) or pneumonia (23%).2 Involvement of other structures can result in the superior vena cava syndrome (6%); dyspnea and hemoptysis due to compression of the pulmonary veins; pulmonary hypertension and cor pulmonale due to pulmonary artery compression; hoarseness due to recurrent laryngeal nerve involvement (2%); dysphagia (2%) and upper gastrointestinal bleeding due to esophageal involvement; and angina due to encasement of the aorta and its branches.2,5 Aside from the aforementioned signs and symptoms, findings on physical examination rarely add any additional diagnostic information. Most commonly, plain radiography of the chest will indicate the presence of a hilar mass (39%), parenchymal opacities (30%), and widening of the medias-
ASSESSMENT The patient’s white blood cell count, serum chemistries, and liver enzymes were unremarkable. A Doppler ultrasound confirmed the presence of deep vein thrombosis in the affected arm. Mediastinal widening with a small infiltrate in the left upper lung was evident in an initial radiograph (Figures 1 and 2). The infiltrate adjoined a 3⫻8 cm mass in the anterior mediastinum that was compressing the left brachiocephalic vein, according to a computed tomograpy (CT) scan (Figures 3 and 4). Blood tests for HIV, antinuclear antibody, and rheumatoid factor were negative, as was a urine test for Histoplasma polysaccharide antigen. Bronchoscopy, done to evaluate the left upper lobe, showed normal airways; culture and staining, including an acid-fast stain, of lavage samples were negative for fungi and bacteria. Four transbronchial biopsies from the same region were unremarkable. A CT-guided biopsy of the mediastinal mass showed fibrosis with spindle cells. Thoracotomy was performed, and the surgical biopsy specimen showed diffuse fibrosis, with granulation tissue and vascular proliferation. There was no evidence of malignancy, and no acid-fast bacilli or granulomas were seen. The Gomori methenamine silver stain displayed extracellular yeast forms, 2 to 4 microns in diameter, compatible with the fungus Histoplasma capsulatum (Figure 5). Requests for reprints should be addressed to Divay Chandra, MD, Department of Internal Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail address: [email protected]
0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.05.020
582
The American Journal of Medicine, Vol 119, No 7, July 2006
Figure 1 The initial chest radiograph (posterio-anterior view) showed widening of the mediastinum with a small infiltrate in the left upper lung.
tinum (28%).2 Occasionally, pulmonary artery enlargement, cardiomegaly, pleural effusion, and lung volume loss are noted.2 CT scans confirm the presence of a mass and provide detailed information about the extent of involvement of mediastinal structures. Currently, magnetic resonance imaging offers no advantage over CT in diagnosis or in defining the status of mediastinal structures.1 Establishing the diagnosis can be quite difficult and generally requires a surgical procedure. Tumors such as Hodgkin’s lymphoma, which can cause extensive fibrosis, cannot be ruled out with confidence on the smaller biopsy specimens obtained by minimally invasive techniques. Identifying the underlying cause for the mediastinal fibrosis
Figure 2
This is the lateral view.
Figure 3 An infiltrate in the left upper lobe was also visible on the first computed tomography (CT) scan with contrast. The right brachiocephalic vein (1), the brachiocephalic artery (2), the left common carotid (3), and the left subclavian artery (4) can be seen as well.
can be challenging as well. When infections are responsible, the usual markers are absent because the acute phase of the infection resolved many years prior to presentation. In one series by Loyd et al, 65% of cases (22/34) had a positive serum complement fixation test, defined as a titer greater than 1:32, at diagnosis.2 Notably, the test was negative in the remaining 35% (12/34), who had either histology or cultures positive for H. capsulatum. No data exists on the sensitivity or specificity of the urine Histoplasma antigen test; however, we do not expect it to be particularly useful because of the remoteness of the acute infection.
Figure 4 The CT scan delineated a retrosternal mass (1), the right brachiocephalic vein (2) at the level of the junction (3) with the left brachiocephalic vein, and the upper part of the arch of the aorta (4).
Chandra et al
583 et al, 21 of 71 patients (30%) died; 9 of these deaths were perioperative.2 Another study reported a mortality rate of 20%, with all the deaths occurring in the perioperative period.4 It is unclear how the availability of the new minimally invasive techniques would affect this high mortality rate. Our patient started a 3-month course of itraconazole and a warfarin regimen. Her arm swelling improved with anticoagulation, and the mass remained radiologically stable over 7 months of follow up.
ACKNOWLEDGEMENTS:
Figure 5 Gomori methenamine silver staining (⫻400) of surgically-obtained mediastinal tissue showed ovoid extracellular yeast (arrow), 2-4 m in diameter with narrow-based budding (H. capsulatum).
Ordinarily, the definitive diagnosis would be made when cultures are positive, or the organism is seen on pathology, as mentioned previously.
MANAGEMENT Treatment options are few, and their efficacy is limited. Alternatives include anti-inflammatory and antifungal agents, and procedures to salvage the involved mediastinal structures. Anti-inflammatory treatment with corticosteroids has not proven to be of any benefit.6,7 Antifungal treatment with the azole drugs is controversial. Itraconazole is considered the drug of choice for H. capsulatum infection and may have some role when features of ongoing or recurrent infection are present in the form of fever and other systemic symptoms.4,8 Treatment for symptomatic involvement of the central vasculature and airways has traditionally involved open surgical resection and reconstruction. These surgeries are technically challenging due to the dense fibrosis in the mediastinum, and as a result, they are associated with high perioperative mortality (up to 20%).4 Newer minimally invasive procedures are being developed, including endoluminal stenting of vascular structures and bronchoscopic stenting of compressed airways.9-11 Survival is difficult to estimate due to the small volume of data and lack of adequate follow up. In the series by Loyd
We would like to acknowledge Bobby L Boyanton, MD, Department of Pathology, Baylor College of Medicine, Houston, Tex, for assistance with histopathology, and Joan Hacken, MD, Department of Radiology, Baylor College of Medicine and Michael E. DeBakey, MD, Veterans Affairs Medical Center, Houston, Tex, for assistance with the radiology images.
References 1. Rossi SE, McAdams HP, Rosado-de-Christenson ML, Franks TJ, Galvin JR. Fibrosing mediastinitis. Radiographics. 2001;21:737-757. 2. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine (Baltimore). 1988;67:295-310. 3. Schowengerdt CG, Suyemoto R, Main FB. Granulomatous and fibrous mediastinitis. A review and analysis of 180 cases. J Thorac Cardiovasc Surg. 1969;57:365-379. 4. Mathisen DJ, Grillo HC. Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg. 1992;54:1053-1058. 5. Holman WL, Sethi GK, Scott SM. Coronary artery bypass grafting with unanticipated fibrosing mediastinitis. Ann Thorac Surg. 1990;49: 321-322. 6. Gran JT. Chronic idiopathic mediastinal fibrosis presenting with malaise, pleuritis and thoracic back pain. Br J Rheumato. 1993;32:757759. 7. Dines DE, Payne WS, Bernatz PE, Pairolero PC. Mediastinal granuloma and fibrosing mediastinitis. Chest. 1979;75:320-324. 8. Maholtz MS, Dauber JH, Yousem SA. Case report: fluconazole therapy in histoplasma mediastinal granuloma. Am J Med Sci. 1994;307: 274-277. 9. Doyle TP, Loyd JE, Robbins IM. Percutaneous pulmonary artery and vein stenting: a novel treatment for mediastinal fibrosis. Am J Respir Crit Care Med. 2001;164:657-660. 10. Fontaine AB, Borsa JJ, Hoffer EK, Bloch RD, So C. Stent placement in the treatment of pulmonary artery stenosis secondary to fibrosing mediastinitis. J Vasc Interv Radiol. 2001;12:1107-1111. 11. Watkinson AF, Hansell DM. Expandable Wallstent for the treatment of obstruction of the superior vena cava. Thorax. 1993;48:915-920.