Pulmonary Medicine

Non-neoplastic Disorders of the Mediastinum: Chronic Mediastinitis

What every physician needs to know:

Chronic mediastinitis results from an inflammatory reaction of the mediastinal lymph nodes, usually in response to prior Histoplasma capsulatum infection. Chronic mediastinitis can manifest as a mediastinal granuloma or, less commonly, as fibrosing mediastinitis. Fibrosing mediastinitis is a mass-like fibrotic reaction that can compress mediastinal structures like the tracheobronchial tree or the great vessels. Erosion into blood vessels can cause hemoptysis. Treatment is largely surgical for symptomatic cases.

Classification:

Chronic forms of mediastinitis include mediastinal granulomas and fibrosing mediastinitis. Mediastinal granuloma, the more common process, presents as an encapsulated mass of coalesced lymph nodes. Fibrosing mediastinitis results from an extensive hypersensitivity response to instigating triggers. Cases of fibrosing mediastinitis can be further subdivided into two patterns of distribution; by far, the more common presentation is focal lesions involving the right paratracheal and subcarinal regions.

Are you sure your patient has chronic mediastinitis? What should you expect to find?

Mediastinal granuloma radiographically presents as a large mediastinal mass. While benign, it can cause symptoms that are due to mass-effect compression of mediastinal structures, resulting in symptoms from airway compression or superior vena cava (SVC) syndrome. Calcified nodes can also erode into the airway wall, resulting in broncholithiasis, obstructive symptoms, and hemoptysis.

The hallmark feature of fibrosing mediastinitis is the presence of dense fibrotic tissue in the mediastinum. Symptoms are largely due to mass-effect from mediastinal fibrosis obstructing adjacent mediastinal structures. Symptoms of the central airways are dyspnea, recurrent or post-obstructive pneumonia, and atelectasis. Hemoptysis can result from involvement of the airway mucosa, erosion into blood vessels, or pulmonary hypertension from obstruction of pulmonary vessels. Symptoms from esophageal involvement include dysphagia, odynophagia, or others if an esophageal fistula develops.

Fibrosing mediastinitis can cause SVC syndrome, which results in swelling in the face, arms, and neck. Some reports attribute a higher rate of SVC syndrome to mediastinal granuloma. Symptoms resulting from involvement of the pulmonary vessels include progressive or exertional dyspnea and hemoptysis. Chronic occlusion of pulmonary veins can result in secondary pulmonary arterial hypertension and cor pulmonale. Other less common symptoms are fever and weight loss.

Beware: there are other diseases that can mimic chronic mediastinitis.

Other diagnoses that may have a similar radiographic presentation include malignancies like small-cell lung cancer, lymphoma, and germ cell tumors. Fungal or mycobacterial infections, sarcoidosis, silicosis, and paraffin (late sequelae of tuberculosis plombage) can also appear similar to chronic mediastinitis.

Biopsy demonstration of fibrosis in the mediastinal space can also occur with sclerosing non-Hodgkins lymphoma, Hodgkins lymphoma (nodular sclerosis), spindle cell tumors, thymoma, thymic carcinoid, simple fibrosis, fibromatosis, and low-grade sarcoma. Needle biopsy may not be adequate to exclude these other diagnoses so open biopsy with extensive tissue sampling and pathology evaluation is needed to differentiate between chronic mediastinitis and other causes of mediastinal fibrosis.

How and/or why did the patient develop chronic mediastinitis?

The exact cause of chronic mediastinitis is unclear. Fibrosing mediastinitis is thought to be the consequence of a hypersensitivity immune response to H. capsulatum or other inciting agents, resulting in abnormal proliferation of dense acellular collagen and fibrous tissue within the mediastinum. Fibrosing mediastinitis is not likely to represent active infection, as organisms cannot be identified in a majority of tissue samples. The most common associated infectious agent is H. capsulatum, which is endemic to the central, southeastern, and mid-Atlantic regions of the United States.

Mycobacterium tuberculosis is a less common cause, while other fungi, autoimmune disorders, silicosis, familial multifocal fibrosclerosis, and methylsergide have also been described as rare causative agents. Only a small minority of patients with mediastinal infections develop fibrosing mediastinitis. It is estimated that more than 500,000 people are infected with H. capsulatum in the United States annually, and over 80 percent of people living in endemic regions are positive for the Histoplasma skin test. Nevertheless, less than 1 percent of patients with histoplasmosis develop fibrosing mediastinitis.

A large study demonstrated two predominant patterns of fibrosing mediastinitis. Eighty-three percent of patients with fibrosing mediastinitis demonstrated a localized disease process that usually affected the right paratracheal and subcarinal regions. Sixty-three percent of these lesions were calcified. Patients with this presentation typically had evidence of prior histoplasmosis or tuberculosis. The remaining 18 percent of patients presented with a diffuse noncalcified infiltrative fibrotic process that involved multiple mediastinal compartments.

These patients had a strong association with other idiopathic inflammatory fibrotic processes like retroperitoneal fibrosis, rather than prior granulomatous disease. The differences in these two patterns of disease suggest that fibrosing mediastinitis may be comprised of two different disease processes: the predominant type (in the United States) in response to prior granulomatous infection versus a less common, more diffuse, idiopathic process.

Mediastinal granuloma, on the other hand, is composed of conglomerations of enlarged lymph nodes that result from direct infection by the H. capsulatum organism. These nodes are encapsulated and contain fibrous or caseous material.

There is some suggestion that mediastinal granuloma and fibrosing mediastinitis may represent a spectrum of disease, as one small case series describes the development of fibrosing mediastinitis in 34 percent of patients with mediastinal granuloma within a two-year period. However, a review of the medical literature by Loyd, et al. did not support a connection between the two entities, aside from their association with prior histoplasmosis.

Which individuals are at greatest risk of developing chronic mediastinitis?

It is unclear why only a small minority of patients with histoplasmosis develop fibrosing mediastinitis. A possible association with the HLA-A2 antigen suggests that genetics may influence development of the disease.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Histoplasma antigen testing is useful in determining a patient's prior exposure to the fungus, but this test is not specific for chronic mediastinitis, as few patients with histoplasmosis develop chronic mediastinitis. Similarly, testing for other infectious agents, such as tuberculosis, is also non-specific.

What imaging studies will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Computed tomography (CT) of the chest with contrast is helpful in delineating mediastinal structures, including soft tissue abnormalities and vascular structures. Magnetic resonance imaging (MRI) can also be used to evaluate mediastinal structures. CXR is nonspecific, and it most commonly demonstrates enlargement of the mediastinum and lymphadenopathy in the subcarinal, right paratracheal, and right hilar regions. Calcifications are seen in up to 86% of cases. Other possible radiographic findings include vascular congestion related to obstruction of the SVC or pulmonary vessels, parenchymal infiltrates/atelectasis, and narrowing of the large airways from central airway obstruction.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Chronic fibrosing mediastinitis is suggested in patients with the right clinical history and radiographic findings consistent with the disease. The lack of calcifications increases the possibility of other diagnoses, however. In addition, tissue sampling is often necessary to exclude other differential diagnoses such as malignancies, sarcoidosis, or infections, as radiographic findings are non-specific.

What diagnostic procedures will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Tissue biopsy is necessary for diagnosis of the disease and exclusion of other differential diagnoses. Mediastinal granulomas will demonstrate caseating granulomas on histology, while fibrosing mediastinitis will demonstrate an exuberant dense fibrosis, with plasma cells and lymphocytes, hyalinized collagen, and sometimes granulomas encasing mediastinal structures.

Endoscopic biopsy (bronchoscopy or EGD) can be used to obtain fine-needle aspirates and sometimes core samples, often utilizing ultrasound guidance techniques. Although small tissue samples limited by the gauge of the endoscopic biopsy needle may limit pathology interpretation, these endoscopic biopsies are useful in excluding malignancies and active infections.

Large tissue samples are typically required to make the diagnosis of fibrosing mediastinitis and to rule out diseases with similar presentations. Extensive diagnostic tissue sampling can be obtained via mediastinoscopy, video-assisted thoracoscopic surgery (VATS), or thoracotomy. Care should be taken since associated pulmonary hypertension increases the risk of hemorrhage.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of chronic mediastinitis?

Tissue specimens demonstrate an infiltrating, fibrotic process. One descriptor of findings divides pathology findings into three classifications. These histologic classes are only descriptive and have not been shown to be predictive of clinical outcomes.

  • Stage I: predominance of edematous fibromyxoid tissue

  • Stage II: presence of eosinophilic hyaline material that forms a glassy band that surrounds and infiltrates mediastinal structures

  • Stage III: dense paucicellular collagen that obliterates other structures, which is the classic microscopic feature of fibrosing mediastinitis

Pathology evaluation is also helpful in excluding other possible differential diagnoses. Spindle cell tumors (localized fibrous tumors of the pleura, diffuse desmoplastic malignant mesothelioma) have more cellularity than fibrosing mediastinitis does. CD34 and bcl-2 staining for localized fibrous tumors of the pleura and keratin staining for mesothelioma are also useful. Metastatic carcinomas, thymic carcinoid, and thymoma are also positive for keratin stain.

If you decide the patient has chronic mediastinitis, how should the patient be managed?

Treatment is largely based on symptoms. Surgical resection can be considered for mediastinal granulomas that cause compression. Calcified broncholiths that erode into the tracheobronchial tree should not be removed bronchoscopically because of the risk of catastrophic bleeding after they are removed from the airway wall. Surgical resection should be considered where surgical control of the vascular structures can be obtained.

In fibrosing mediastinitis, only case reports or small series have described the use of antifungal agents, and the paucity of data limits the use of such agents as a widespread approach. Most studies show little support for the use of steroids despite the supposition that fibrosing mediastinitis stems from an aggressive fibrotic immune response. Given the high level of morbidity associated with surgical intervention, localized therapeutic interventions are now used for relief of symptoms: bypass vein grafts and endovascular grafts can alleviate SVC syndrome, therapeutic bronchoscopic dilation and stenting are used for airway obstruction, and surgical closure or stenting can be performed for tracheoesophageal fistulas or esophageal compression.

What is the prognosis for patients managed in the recommended ways?

Chronic granulomas are often benign and usually do not have a significant detrimental impact on patient longevity. However, fibrosing mediastinitis is a chronic but potentially progressive process; several small case series describe upwards of 30 percent mortality within six years of onset of symptoms, despite therapy. Mortality is typically related to complications from hemoptysis, recurrent infections, or cor pulmonale.

What other considerations exist for patients with chronic mediastinitis?

Primary considerations for the diagnosis and treatment of the disease have been outlined above.

What’s the evidence?

Akman, C, Kantarci, F, Cetinkaya, S. "Imaging in mediastinitis: a systematic review based on aetiology". Clin Radiol. vol. 59. 2004. pp. 573-585.

(Review of radiographic findings associated with mediastinitis.)

Devaraj, A, Griffin, N, Nicholson, A. "Computed tomography findings in fibrosing mediastinitis". Clin Radiol. vol. 62. 2007. pp. 781-786.

(Radiographic findings associated with fibrosing mediastinitis in a case series.)

Dines, D, Payne, W, Bernatz, P. "Mediastinal granuloma and fibrosing mediastinitis". Chest. vol. 75. 1979. pp. 320-324.

(Case series of patients with mediastinitis.)

Dunn, EJ, Ulicny, KS, Wright, CB. "Surgical implications of sclerosing mediastinitis: a report of six cases and review of the literature". Chest. vol. 97. 1990. pp. 338-346.

(Case series of patients with mediastinitis.)

Flieder, D, Suster, S, Moran, C. "Idiopathic fibroinflammatory (fibrosing/sclerosing) lesions of the mediastinum: a study of 30 cases with emphasis on morphologic heterogeneity". Mod Pathol. vol. 12. 1999. pp. 257-264.

(Pathology review of a case series of thirty patients with fibrosing mediastinitis.)

Lloyd, J, Tillman, B, Atkinson, J. "Mediastinal fibrosis complicating histoplasmosis". Medicine. vol. 67. 1988. pp. 295-310.

(Clinical and radiographic summary of a case series of seventy-one patients with fibrosing mediastinitis.)

Manali, E, Saad, C, Krizmanich, G. "Endobronchial findings of fibrosing mediastinitis". Respir Care. vol. 48. 2003. pp. 1038-1042.

(Case descriptions of endobronchial findings associated with mediastinitis.)

Mathisen, DJ, Grillo, HC. "Clinical manifestation of mediastinal fibrosis and histoplasmosis". Ann Thorac Surg. vol. 54. 1992. pp. 1053-1057.

(Summary of findings of a case series of patients undergoing surgical intervention for fibrosing mediastinitis.)

Mole, TM, Glover, J, Sheppard, MN. "Sclerosing mediastinitis: a report on 18 cases". Thorax. vol. 50. 1995. pp. 280-283.

(Summary of findings of eighteen cases of fibrosing mediastintis.)

Rodriguez, E, Soler, R, Pombo, F. "Fibrosing mediastinitis: CT and MR findings". Clin Radiol. vol. 53. 1998. pp. 907-910.

(Case descriptions of radiographic findings associated with fibrosing mediastinitis.)

Rossi, SE, McAdams, H, Rosado-de-Christenson, M. "Fibrosing mediastinitis". Radiographics. vol. 21. 2001. pp. 737-757.

(Radiographic and pathologic review of fibrosing mediastinitis.)

Sherrick, A, Brown, L, Harms, G. "The radiographic findings of fibrosing mediastinitis". Chest. vol. 106. 1994. pp. 484-489.

(Retrospective review of radiographic findings in eleven patients.)

Urschel, HC, Razzuk, MA, Netto, GJ. "Sclerosing mediastinitis: improved management with histoplasmosis titer and ketoconazole". Ann Thorac Surg. vol. 50. 1990. pp. 215-221.

(Retrospective review of the role of complement fixation titers and ketoconazole therapy in the treatment of patients with fibrosing mediastinitis from histoplasmosis.)
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